WO2020041741A1 - Thyroid hormone receptor beta agonist compounds - Google Patents

Thyroid hormone receptor beta agonist compounds Download PDF

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Publication number
WO2020041741A1
WO2020041741A1 PCT/US2019/047968 US2019047968W WO2020041741A1 WO 2020041741 A1 WO2020041741 A1 WO 2020041741A1 US 2019047968 W US2019047968 W US 2019047968W WO 2020041741 A1 WO2020041741 A1 WO 2020041741A1
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Prior art keywords
substituted
compound
methyl
oxo
alkyl
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PCT/US2019/047968
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French (fr)
Inventor
Thorsten A. Kirschberg
Randall HALCOMB
Yingzi XU
F. Anthony Romero
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Terns, Inc.
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Priority to CA3110520A priority Critical patent/CA3110520A1/en
Priority to JP2021533405A priority patent/JP2021535207A/en
Priority to EP19852050.4A priority patent/EP3840755A4/en
Priority to CN201980066702.0A priority patent/CN112805005A/en
Priority to AU2019325656A priority patent/AU2019325656A1/en
Publication of WO2020041741A1 publication Critical patent/WO2020041741A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • This invention relates to compounds, preferably thyroid hormone receptor beta (TOR beta) agonist compounds, compositions thereof, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by TOR beta.
  • TOR beta thyroid hormone receptor beta
  • THR beta diseases or disorders associated with THR beta include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty' liver disease (NAFLD), metabolic syndrome, dyshpidemia, hypertriglyceridemia, and hypercholesterolemia.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty' liver disease
  • metabolic syndrome dyshpidemia
  • hypertriglyceridemia hypertriglyceridemia
  • hypercholesterolemia hypercholesterolemia
  • thyroid hormone analogs such as those that are THR beta agonists, and preferably those that avoid the undesirable effects of hyperthyroidism and hypothyroidism, and maintain the beneficial effects of thyroid hormones, e.g., for the treatment for patients with non-alcoholic steatohepatitis (NASH) in particular, there is a need to develop new thyroid hormone analogs that are selective agonists for THR beta, and preferably those that avoid the undesirable effects associated with agonism of THR alpha, and maintain the beneficial effects of thyroid hormones, e.g., for the treatment for patients with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia.
  • NASH non-alcoholic steatohepatitis
  • ring A together with the carbonyl (keto) group within the ring fonn a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting ofN, O, and S, wherein the heterocycle is optionally substituted with 1-2 Ci-C-3 alkyl or C3-C4 cycloalkyl groups, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
  • R 1 is C1-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups, C 3 -C5 cycloalkyl, CON (R 10 )2, or NR 10 CQR 10 ;
  • R 2 is H or Ci-C 3 alkyl
  • L is O, CT-fc, S, SO, SO2, CO, CHF, CF 2 , O R )C ⁇ .
  • R 3 and R 4 are independently Cl, Br, methyl, or ethyl
  • R 5 together with R 4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
  • X is absent, O, NR i2 , C(0)NR 12 , NR i2 C(G), CR 12 R 12 , 0( R ’ R CR i2 R I2 Q, NR 12 CR 12 R 12 , CR i2 R !2 NR 12 , SO2NR 12 , or ⁇ R - ' SO ⁇ :
  • each R 10 is independently C1-C 3 alkyl or H;
  • each R 11 is independently C1-C2 alkyl optionally substituted with 1-5 halo, or two R 11 groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring;
  • each R 12 is independently H or methyl.
  • the compound is of formula (IIA) or (PB):
  • R 1 , R 2 , R 3 , R 4 , R 3 , X, and L are as defined for the compound of formula (I).
  • the compound is of formula (VD):
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1.
  • R 1 is C1-C4 alkyl optionally substituted with 1-2 halo or hydroxyl groups, or C3-C5 cycloalkyl. In some embodiments, R 1 is isopropyl, t-butyl,
  • R 2 is H or -CH3.
  • R 3 is chloro or -CH3.
  • R 4 is chloro or -CIT; or R 5 together with R 4 and the intervening atoms form a 5-6 membered cycloalkyl.
  • R 3 together with R 4 and the intervening atoms form cyclopentyl.
  • R 5 is H or fluoro.
  • X is a bond. In some embodiments, X is NR !2 C(0), OCR 12 R 12 , or NR 12 CR 12 R 12 ; and each R 12 is independently H or methyl. In some embodiments, X is
  • L is O, CH2, SO2, CO, CHR 11 , or C(R n )R n ; and each R 1 1 is independently methyl or ethyl. In some embodiments, L is O, CHb, SO2, or CO.
  • provided herein is a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound provided herein and at least one pharmaceutically acceptable excipient.
  • THR beta agonizing thyroid hormone receptor beta
  • a method of treating a disorder which is mediated by THR beta in a patient comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • the disorder is non-alcoholic steatohepatitis (NASH).
  • compositions and methods include the recited elements, but not excluding others “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination.
  • a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of’ shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.
  • Effective amount or dose of a compound or a composition refers to that amount of the compound or the composition that results in an intended result as desired based on the disclosure herein. Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., and without limitation, by determining the LDso (the dose lethal to 50 % of the population) and the EDso (the dose therapeutically effective in 50 % of the population).
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
  • Various substances may be embraced by the tenn excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral
  • Binders include, e.g., carbomers, povidone, xanthan gum, etc.;
  • disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.
  • creams or lotions include, e.g., maltodextrin, carrageenans, etc.
  • lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl furnarate, etc.
  • materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.
  • suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.
  • sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc
  • Patient refers to mammals and includes humans and non-human mammals.
  • patient examples include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.
  • “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.
  • “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt.
  • Prodrug refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
  • a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
  • a prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
  • prodrug may be synthesized using reactants oilier than employing the corresponding drug.
  • prodrags include, carboxy esters, linear and cyclic phosphate esters and phosphoramide and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates where the hydroxy group is part of an aryl or heteroaryl moiety, where the aryl and heteroaryl may be optionally substituted), and the likes.
  • Salt refers to an ionic compound formed between an acid and a base.
  • salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts.
  • ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NHg Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
  • such salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
  • “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a patient. The results may require multiple doses of the compound or the composition.
  • Treating” or“treatment” of a disease in a patient refers to 1) preventing die disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • “treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient.
  • ‘'treatment” is a reduction of pathological consequence of the disease or disorder.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • An“isotopomer” of a compound is a compound m winch one or more atoms of the compound have been replaced with isotopes of those same atoms.
  • H has been replaced by D or T
  • !2 C has been replaced by ! 1 C
  • i4 N has been replaced by !5 N.
  • replacement of with D can in some instances lead to reduced rates of metabolism and therefore longer half-lives.
  • Replacement of H with T can provide radioligands potentially useful in binding studies.
  • Replacement of i2 C with the short-lived isotope n C can provide ligands useful in Positron Emission Tomography (PET) scanning.
  • PET Positron Emission Tomography
  • Replacement of i4 N with i5 N provides compounds that can be detected/monitored by 15 N NMR spectroscopy.
  • an isotopomer of a compound containing -CH2CH3 is that compound but containing -CD2CD3 instead of the -CH2CH3.
  • the disclosure includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (where H can be 2 H, i.e., D).
  • Isotopologues can have isotopic replacements at any or at all locations in a structure, or can have atoms present in natural abundance at any or all locations in a structure.
  • Stereoisomer or“stereoisomers” refer to compounds that differ in the stereogenicity of the constituent atoms such as, without limitation, in the chirality of one or more stereocenters or related to the cis or trans configuration of a carbon-carbon or carbon-nitrogen double bond.
  • Stereoisomers include enantiomers and diastereomers.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyi groups having from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, and more preferably from 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyi groups such as methyl ( ⁇ 3 ⁇ 4-), ethyl (CH3CH2-), «-propyl (CH3CH2CH2-), isopropyl ((CH ⁇ CH-), «-butyl (CH3CH2CH2CH2-), isobutyl ((CH ⁇ CHCHz-), sec-butyl ((CHsXCH ft CH-), i-butyl ((( ‘ 1 Md.
  • Cx alkyl refers to an alkyl group having x number of carbon atoms.
  • Cx alkenyl refers to an alkenyl group having x number of carbon atoms.
  • Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aeyioxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonyl amino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryioxy, arylthio, substituted arylthio, arylamino, substituted arydamino, heteroarylammo, substituted heteroarylamino, eycloalkyiamino, substituted cycloalkylamino,
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyioxy, ammo, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminotliiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted aiylamino, heteroarylamino, substituted heteroarylamino, cycioaikylamino, substituted cycloaikylammo,
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyioxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminotliiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy 7 , substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycioaikylamino, substituted cycioaikylamino, substituted cycioaikylamino, substitute
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, f-butoxy, xeobutoxy, and o-pentoxy.
  • Substituted alkoxy refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
  • Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Acyl refers to the groups 1 !-( (())-. alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl -C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, wherein al
  • R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, and, substituted aryl, heteroaiyd, substituted
  • Acyloxy refers to the groups alkyl-C(0)0-, substituted alkyl ⁇ C(Q)Q-,
  • R 31 and R 32 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 31 and R 32 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein .
  • R 31 is hydrogen and R 32 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 32 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 3i or R 32 is hydrogen but not both.
  • R 31 nor R 32 are hydrogen
  • Aminocarbonyl refers to the group -C(0)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic
  • Aminothiocarbonyl refers to the group -C(S)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted and, heteroaryl, substituted heteroaryl, substituted heteroary
  • Aminocarbonylamino refers to the group -NR 30 C(O)NR 33 R 34 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalky], or substituted cycloalky], and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitute
  • Aminothiocarbonylamino refers to the group -NR 30 C(S)NR 33 R 34 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alk
  • Aminocarbonyloxy refers to the group -0-C(0)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryl, heteroary
  • Aminosulfonyloxy refers to the group -0-S02NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, a ryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted aikynyi, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryi,
  • Aminosulfonylamino refers to the group -NR 30 -SO2NR 33 R 34 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryi, substituted heteroaryi, cycloalkyi, or substituted cycloalkyi, and R 33 and R J4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and w'here R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g, phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom.
  • Preferred aryl groups include phenyl and naphthyl.
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryioxy, arylthio, substituted arylthio, arylaniino, substituted aryiamino, heteroarylamino, substituted heteroarylamino, cycloalkyla
  • heterocycloalkylamino substituted heterocyclylamino carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidmo, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroaryithio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocycly!oxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthi
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Arylamino refers to the group -NR 3 '(aryl), where aryl is as defined herein and R 37 is hydrogen, alkyl, or substituted alkyl.
  • Substituted arylamino refers to the group -NR 37 (substituted aryl), where R 37 is hydrogen, alkyl, or substituted alkyl where substituted aryl is as defined herein.
  • Carboxy or“carboxyl” refers to -COOH or salts thereof.
  • Carboxyl ester or“carboxy ester” refers to the groups -C(0)0-alkyl
  • -C(0)0-substituted alkyl -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted cycloalkyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)amino refers to the group -NR 30 -C(O)O-alkyl
  • R J0 is alkyl or hy drogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted alkyl, -0-C(0)0 ⁇ alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0 ⁇ alkyny!,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Cyano refers to the group -CoN.
  • Cycloalkyl refers to saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms, having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • C x cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • One or more the rings can be aryl, heteroaryl, or heterocyclic pro vided that the point of atachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring.
  • “Substituted eycloalkyi” refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acy!oxy, am o, substituted amino, aminocarbonyl, aminotliioearbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
  • Cycloalkylamino refers to the group -NR 37 (cycloalkyl) where R 37 is hydrogen, alkyl, or substituted alkyl.
  • Substituted cycloalkylamino refers to the group -NR 37 (substituted cycloalkyl) where R 37 is hydrogen, alkyl, or substituted alkyl and substituted cycloalkyl is as defined herein.
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • each R 36 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R 36 groups attached to a common guanidino nitrogen atom are optionally joined toge ther with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R 36 is not hydrogen, and wherein said substituents are as defined herein.
  • "Halo" or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • Heteroalkylene refers to an alkylene group wherein one or more carbons is replaced with -0-, -S-, SO ⁇ . -N R 0 -.
  • substituted heteroalkylene refers to heteroalkynylene groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g. , indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N 0), sulfinyl, or sulfonyl moieties.
  • Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl.
  • Other preferred heteroaryls include 9 or 10 membered heteroaryls, such as indolyl, qu ohnyl, quinolonyl, isoquinolinyl, and isoquinolonyl.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Substituted heteroaryloxy refers to the group -O -(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl .
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • Heteroarylamino refers to the group -NR 37 (heteroaryl) where R 3 7 is hydrogen, alkyl, or substituted alkyl .
  • “Substituted heteroarylamino” refers to the group -NR 37 (substituted heteroaryl), where R 37 is hydrogen, alkyl, or substituted alkyl and substituted heteroaryl is defined as herein.
  • “Heterocycle” or “heterocyclic” or“heterocycloalkyl” or“heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, and from 1 to 4 ring heteroatoms, preferably from 1 to 3 heteroatoms, and more preferably from 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen Cx
  • heterocycloalkyl refers to a heterocycloalkyl group having x number of ring atoms including the ring heteroatoms.
  • Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems.
  • fused ring systems one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N -oxide, sulfmyi, sulfonyl moieties.
  • Heterocyciylene refers to a divalent saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
  • Substituted heterocyciylene refers to heterocyciylene groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl
  • Substituted heterocyclic or“substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl).
  • Heterocyclylthio refers to the group -S-heterocyey!.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl).
  • Heterocyclylamino refers to the group -NR3 7 (heterocyclyl) where R 37 is hydrogen, alkyl, or substituted alkyl.
  • Substituted heterocyclylamino refers to the group -NR 37 (substituted heterocyclyl), where R 37 is hydrogen, alkyl, or substituted alkyl and substituted heterocyclyl is defined as herein.
  • heterocyclyl and heteroaryl include, but are not limited to, azetidinyl, pyrrolyl, imidazo!yl, pyrazoly!, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl, phthaiazinyi, naphthylpyridmyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carboimyl, phenanthridinyl, acridinyl, phenanthrolinyi, isothiazoiyl, phenazinyl, isoxazolyl, phenoxa
  • thiamorpholinyl 1,1-dioxothiomorpholinyl, piperidinyl, pyrcolidinyl, and tetrahydrofuranyl.
  • Niro refers to the group -NO2.
  • “Spiro ring systems” refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
  • Substituted sulfonyl refers to the group -SCh-alkyl, -SC -substituted
  • alkyl -SO2-QH, -S02-alkenyl, -S02-substituted alkenyl, -SG2-cycloalkyl, -S02-substituted cylcoalky], -SQr-aryl, -SCh-substituted aryl, -SC -heteroaxyl, -S02-substituted
  • heteroaryl -SC -heterocyclic, -SOz-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Substituted sulfonyl includes groups such as methyl-SC -, phenyl-SC -, and -rnethylphenyl-SO .
  • Preferred substituted alkyl groups on the substituted alkyl-SCh- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyi, difluromethyl, fluoromethyl and the like.
  • Substituted sulfinyi refers to the group -SO-alkyl, -SO-substituted
  • alkyl -SO-alkenyl, -SO-substituted alkenyl, -SQ-cycloalkyi, -SO-substituted
  • heteroaryl -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Substituted sulfinyi includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.
  • Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyi, difluromethyl, fluoromethyl and the like.
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted and, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • “Sulfonylamino” refers to the group -NR 37 ( substituted sulfonyl) where R 57 is hydrogen, alkyl, or substituted alkyl and substituted sulfonyl is as defined here.
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-,
  • cycloalkyl C(S)- substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-,
  • heteroaryl-C(S)- substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted
  • heterocyclic-C(S)- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Forml refers to the group -C(0)H.
  • Alky!thio refers to the group -S-a!kyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyi and the like.
  • the tenn“optionally substituted” refers to a substituted or unsubstituted group.
  • the substituted group may be substituted with one or more substituents, such as e.g., 1 , 2, 3, 4 or 5 substituents.
  • the substituents are selected from the functional groups provided herein.
  • the substituents are selected from oxo, halo, -CN, NCh, -CO2R 100 , -OR 100 , -SR 100 , -SOR 100 , -SQ2R 100 , -NR i01 R 102 , ⁇ CONR 10i R 102 ,
  • the substituents are selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3 and -OCHF2.
  • R 101 and R 102 independently are hydrogen; C;-Cs alkyl, optionally substituted with
  • each R I independently is hydrogen or CI-CK alkyl; C3-Ci2 cycioalkyl; C4-Cio heterocyclyl; Ce-Cwaryl; or C2-C ] 2 heteroaryl;
  • each cycioalkyl, heterocyclyl, ar ⁇ , or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R !ul and R 102 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • alkoxycarbonylalkyl refers to the group (alkoxy )-C(0)-(alkyl)-.
  • impermissible substitution patterns e.g., methyl substituted with 4 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, wdierein the heterocyle is optionally substituted with 1-2 substituents selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
  • R 1 is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro, or hydroxyl groups; C3-C5 cycloalkyl, CON(R l0 )2, or NR ]ll COR t0 , wherein each R !0 is
  • R 2 is H or C1-C 3 alkyl
  • L is O, P 1 -. S, SO, SO2, CO, CHF, CF 2 , C(R n )CN such as C(Me)CN, CHR 11 , or ( (R )R .
  • R n is C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R 11 groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring;
  • each of R 3 and R 4 is independently Cl, Br, Me, or ethyl;
  • R 3 is H, halo, C1-C4 alkyl preferably Ctb, or C3-C4 cycloalkyl, or R 5 together with R 4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1- 2 ring heteroatoms; and
  • X is absent (i.e., X is a bond), or is O, NR 12 , C(Q)NR !2 , NR i2 C(Q), CR i2 R 12 , OCR i2 R 12 ,
  • the compound of fonnula (I) is a pharmaceutically acceptable salt thereof.
  • the compound of formula (1) is a compound of formula (IIA):
  • the compound of formula (1) is a compound of formula (IIB):
  • the compound of formula (1) is a compound of formula (IPA).
  • the compound of formula (1) is a compound of formula (MB):
  • the compound of formula (I) is a compound of formula (IIIC):
  • the compound of formula (I) is a compound of formula (HID):
  • the compound of formula (I) is a compound of formula (IV A):
  • the compound of formula (I) is a compound of fonnula (IVB):
  • the compound of formula (I) is a compound of fonnula (IV C):
  • the compound of formula (I) is a compound of formula (IVD):
  • the compound of formula (I) is a compound of formula (VA):
  • the compound of formula (I) is a compound of formula (VB):
  • the compound of formula (I) is a compound of formula (VC):
  • the compound of formula (I) is a compound of formula (VD):
  • the compound of formula (I) is a compound of formula (VIA):
  • the compound of formula (I) is a compound of formula (VIB):
  • the compound of formula (I) is a compound of formula (VIC):
  • the compound of formula (I) is a compound of formula (VID):
  • the compound of formula (I) is a compound of formula (VIIA).
  • R 2 is H or methyl, and the variables are defined as in formula (1).
  • the compound of formula (I) is a compound of formula (VHB):
  • R 2 is H or methyl, and the variables are defined as in formula (I).
  • the compound of formula (I) is a compound of formula (VIIC):
  • R 2 is H or methyl, and the variables are defined as in formula (I).
  • the compound of formula (I) is a compound of formula (VIID):
  • R 2 is H or methyl, and the variables are defined as in formula (I).
  • the compound of fonnula (I) is a compound of formula (VIIIA):
  • R 2 is H or methyl, and the variables are defined as in formula (I).
  • the compound of formula (I) is a compound of formula (VIIIB):
  • the compound of formula (I) is a compound of formula (VH!C):
  • the compound of fonnula (I) is a compound of formula (VIIID):
  • the compound of formula (I) is a compound of fonnula (IXA), (IXB), (IXC), (IXD), (IXE), or (IXF): wherein the variables are defined as in formula (I)
  • the compound is of formula (IXA).
  • the compound is of formula (IXB).
  • the compound is of formula (1XC).
  • the compound is of formula (IXD).
  • the compound is of formula (IXE).
  • the compound is of fonnula (IXF).
  • ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein the keto group is not adjacent to the atom attached to X.
  • ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyle is substituted with 1-2 C1-C 3 alkyl or C 3 -C4 cycloalkyl, and wherein the keto group is not adjacent to the atom attached to X
  • the 5 membered heterocycle contains 1 -3 ring heteroatoms selected from the group consisting of N and O.
  • ring A together with the carbonyl (keto) group within the ring is
  • ring A together with the carbonyl (keto) group within the ring
  • R 1 is C1-C4 alkyl. In some embodiments, R 1 is methyl, ethyl, n- propyl, isopropyl, «-butyl, or t-butyl. In some embodiments, R 1 is C3-C4 alkyl. In one embodiment, R ! is isopropyl. In some embodiments, R ! is t-butyl. In one embodiment, R 1 is C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro. In some embodiments, R ! is C1-C4 alkyl optionally substituted with 1-2 halo, such as fluoro or chloro. In one embodiment, R ! is Ci - alkyl optionally substituted with 1-5 halo or hydroxyl groups. In some embodiments, R 1 is methyl, ethyl, n- propyl, isopropyl, «-butyl, or t-butyl. In some embodiments, R 1 is
  • R ! is C2-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups.
  • R 1 is C 1 -C 4 alkyl optionally substituted with 1 -2 halo or hydroxyl groups.
  • R 1 is C1-C4 alkyl optionally substituted with 1 -5 hydroxyl groups. In some embodiments, R ! is Ci-C 4 alkyl optionally substituted with 1-2 hydroxyl groups. In some embodiments, R 1 is C1-C4 alkyl substituted with 1 hydroxyl group. In some embodiments, R 1 is C1-C4 alkyl optionally substituted with 1-2 halo or hydroxyl groups. In some embodiments, R! is HO-CH(CH3)-. In some embodiments, R 1 is HO-CH(CH2CH3)-. In some embodiments, R 1 is H0-C(CH3 ⁇ 2 . In some embodiments, R ! is HO-CH2CH(CH3)-.
  • R 1 is C3- Cs cycloalkyl.
  • R ! is a monocyclic C3-C5 cycloalkyl.
  • R ’! is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R ] is cyclopropyl.
  • R ! is a fused bicyclic C3-C5 cycloalkyl.
  • R 1 is a bridged bicyclic C3-C5 cycloalkyl. some embodiments.
  • R 1 is
  • R 1 is CON(R 10 )2. In one embodiment, R 1 is NR 10 CQR 10 .
  • each R 10 is independently C1-C3 alkyl. In some embodiments, each R 10 is independently methyl, ethyl, «-propyl, or isopropyl. In some embodiments, each R 10 is methyl. In one embodiment, each R !0 is H. In some embodiments, one R 10 is H and the other R i0 is C1-C3 alkyl. In some embodiments, one R 10 is H and the other R 10 is methyl. [0155] In one embodiment, R 2 is H. In one embodiment, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl, ethyl, «-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is H or -CH 3 .
  • L is O. In one embodiment, L is CH2. In one embodiment, L is S. In one embodiment, L is SO. In one embodiment, L is SO2. In one embodiment, L is CO. In one embodiment, L is CHF. In one embodiment, L is CF 2 . In one embodiment, L is C(R n )CN. In one embodiment, L is C(Me)CN.
  • L is CHR !1 or C(R u )R n , wherein each R 11 is independently C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R 11 groups together with the carbon atom they are attached to fonn a cyclopropyl or cyclobutyl ring.
  • L is CHR !1 .
  • L is C(R I ! )R n .
  • each R 11 independently is C1-C2 alkyl, i.e., is methyl or ethyl.
  • each R u independently is C1-C2 alkyl substituted with 1 -5 halo, preferably fluoro.
  • the 2 R u groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring.
  • L is O, CH2, SO2, CO, CHR !! , or C(R U )R !1
  • each R !1 is independently methyl or ethyl.
  • L is O, CH2, SO2, or CO.
  • R 3 is Cl. In one embodiment, R 3 is Br. In one embodiment, R 3 is Me. In one embodiment, R 3 is ethyl. In some embodiments, R 3 is Cl or -CH 3 . In one embodiment, R 4 is Cl. In one embodiment, R 4 is Br. In one embodiment, R 4 is Me. In one embodiment, R 4 is ethyl. In one embodiment, R 3 and R 4 are each Cl. In some embodiments, R 3 and R 4 are each methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some embodiments, R 3 is Br. In one embodiment, R 3 is Me. In one embodiment, R 3 is ethyl. In some embodiment, R 3 and R 4 are each Cl. In some embodiments, R 3 and R 4 are each methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some
  • R 3 is methyl and R 4 is Cl.
  • R 3 is H. In one embodiment, R 3 is halo. In some embodiments,
  • R 5 is fluoro, ch!oro, or bromo. In some embodiments, R 5 is fluoro. In one embodiment, R 5 is C1-C4 alkyl. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl, ethyl, «-propyl, or isopropyl. In one embodiment, R 5 is CH 3 . In some embodiments, R 3 is H or -CH 3 . In one embodiment, R 5 is C.3-C4 cycloalkyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl.
  • R 4 together with R 5 and the intervening atoms form a 5-7 membered cycloalkyl. In some embodiments, R 4 together with R 3 and the intervening atoms form cyclopentyl or cyclohexyl. In some embodiments, R 4 together with R 5 and the intervening atoms form cyclopentyl. In one embodiment, R 4 together with R 5 and the intervening atoms form a 5-7 membered heterocycle containing 1-2 ring heteroatoms. Preferred heteroatoms include one or more of N, O, and S.
  • X is absent (i.e., X is a bond). In one embodiment, X is O. In one embodiment, X is NR 12 . In one embodiment, X is C(0)NR ] 2 . In one embodiment, X is NR i2 C(0). In one embodiment, X is NR i2 S02. In one embodiment, X is SO2NR 12 . In one embodiment, X is NR 12 C(0). In one embodiment, X is CR i2 R !2 . In one embodiment, X is QCR i2 R 12 . In one embodiment, X is CR 12 R i2 Q. In one embodiment, X is CR !2 R i2 NH.
  • X is NR 12 CR 12 R !2 . In some embodiments, X is NR !2 C(0), QCR! 2 R 12 , or NR !2 CR i2 R 12 , and each R 12 is independently H or methyl. In some embodiments, X is N(CH3)CH2. In one embodiment, X is CR 12 R i2 NR ]2 In one embodiment, X is NH. In one embodiment, X is CH2. In one embodiment, X is OCtb. In one embodiment, X is CH2O. In one embodiment, X is NHCH2. In one embodiment, X is CH2NH. In one embodiment, X is NHC(O). In one embodiment, X is C(0)NH.
  • X is SO2NH. In one embodiment, X is NHSO2. In some embodiments, X is OCH2, NHCH2, NHC(O), N(CH3)CH2, or N ⁇ 1 1)0 !((. ' ! 1 ⁇ ⁇ . In one embodiment, R !2 is H. In one embodiment, R !2 is methyl. In some embodiments, all R 12 groups in a given moiety, such as OCR i2 R !2 , are H. In some
  • all R 12 groups in a given moiety are methyl.
  • the R 12 groups in a given moiety, such as QCR 12 R i2 are a combination of H and methyl.
  • R 2 is H or C1-C3 alkyl
  • R J is Cl or methyl
  • R 4 is Cl or methyl
  • R 5 is H, halo, or Ci-Cr alkyl
  • (IX) L is O, CH 2 , SC , or CO.
  • (I) applies. In one variation, (II) applies. In one variation, (III) applies. In one variation, (IV) applies. In one variation, (V) applies. In one variation, (VI) applies. In one variation, (VII) applies. In one variation, (VIII) applies. In one variation, (IX) applies. In one aspect of this variation, (I), (II), (III), (IV), (V), (VI), (VIII), and (IX) apply. In another aspect of this variation, (I), (II), (III), (IV), (VII), (VIII), and (IX) apply. In one variation, (i), (iii), and (vi) apply.
  • (ii), (iii), and (v) apply. In one variation, (i), (in), and (vi) apply. In one variation, (i), (iv), and (vi) apply. In one variation, (1), (iii), (VII), and (vi) apply.
  • the compound of formula (I) is an agonist of THR beta. In some embodiments, the compound of formula (I) is an agonist of TOR beta and is selective over TOR alpha. In some embodiments, the compound of formula (I) has at least 2-fold selectivity for TOR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 5 -fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 10-fold selectivity for TOR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 20-fold selectivity for THR beta over TOR alpha.
  • the compound of formula (I) has at least 50-fold selectivity for THR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 75 -fold selectivity for THR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 100-fold selectivity for TOR beta over THR alpha.
  • the compound of formula (I) has at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold selectivity for TOR beta over THR alpha.
  • selectivity is assessed via a biochemical assay, such as the TR-FRET assay described in Example B 1.
  • a compound selected from the compounds in Table 1, or pharmaceutically acceptable salt thereof is provided.
  • certain compounds described in the present disclosure, including in Table 1, are presented as specific stereoisomers and/or in a non stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1, are herein described.
  • provided herein is a compound selected from those listed in Table 1 or a pharmaceutically acceptable salt thereof.
  • the invention also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein.
  • the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, prodrags, or isotopomers, of the compounds described. Unless stereochemistry' is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds.
  • compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof.
  • Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racernic, non-racemic, enantioenriehed and scalemic mixtures of a compound are embraced.
  • T Br, CN, NH
  • R 1 , R 3 , R 4 , and R 5 are as defined for the compound of formula (I); T is Br, CN, or NHL ⁇ ; and PG and G are suitable protecting groups.
  • the biaryl-ether core of the compounds disclosed herein can be prepared as outlined in Scheme 1. Reaction of 3,6-dichloropyridazine and compounds of general formula R'-CCbH with ammonium persulfate provides R ⁇ substituted dichloropyridazine compounds, which can then be reacted with phenol derivatives, hydrolyzed, and optionally N-protected to provide the desired intermediate compounds.
  • R 1 is as defined for the compound of formula (I).
  • Scheme G provides an alternative synthesis of the pyridazines used for the preparation of compounds of fonnula (I) disclosed herein. Reaction of 3,6-dichloro-l,2,4,5-tetrazine with R ! -substituted acetylenes affords R ! -substituted dichloropyridazine compounds.
  • R 1 , R 3 , R 4 , and R 5 are as defined for the compound of formula (I); and G is a suitable protecting group.
  • Scheme la outlines a synthesis wherein G is an alkyl group and T is Nhb.
  • Compounds having the biaryl-ether core with an amine moiety can undergo phthalimide protection, N- alkylation, and subsequent deprotection to provide the desired intermediate compounds.
  • R 1 , R 3 , R 4 , R 3 , and R 1 -' are as defined for the compound of formula (I); and PG, G, and Gi are suitable protecting groups
  • Scheme 2 outlines the synthesis of certain compounds of formula (I) disclosed herein.
  • Compounds having the biaryl-ether core with an amine moiety can undergo N-alkylation and second amine derivatization, followed by reaction with NH2OH, treatment with a carbonyl transfer reagent, and optional deprotection to afford the desired compounds.
  • R 1 , R 3 , R 4 , R 5 , and R 12 are as defined for the compound of formula (I); and PG and Gi are suitable protecting groups.
  • Scheme 2a outlines an alternative synthesis of certain compounds of formula (1) disclosed herein.
  • Compounds having the biaryl-ether core with an amine moiety can undergo N ⁇ alkylation, protection of the amine group, reaction with NH2OH, treatmen t with a carbonyl transfer reagent, and optional deprotection or hydrolysis to afford the desired compounds.
  • R 1 , R 3 , R 4 , R 5 , and ring A are as defined for the compound of formula (I); and G and Gi are suitable protecting groups
  • Scheme 3 show's the synthesis of certain compounds of formula (I). Reaction of biaryl- ether derivatives containing an amine moiety with carboxylic acid deri vatives of ring A provides amide bond formation to form the desired compounds.
  • Scheme 4 shows the synthesis of certain compounds of formula (I). Reaction of biaryl- ether derivatives containing an amine moiety with carboxylic acid deri vatives of ring A provides amide bond formation to form the desired compounds.
  • R 1 , R 3 , R 4 , R'. and R 12 are as defined for the compound of formula (I); and G and PG are suitable protecting groups.
  • Scheme 4 shows the synthesis of certain compounds of formula (I). Palladium- mediated hydroxylation of biaryl -ether derivatives containing a bromo group, followed by O- alkylation, reaction with NthOH, treatment with a carbonyl transfer reagent, and optional deprotection or hydrolysis provides the desired compounds.
  • Scheme 5 shows the synthesis of certain compounds of formula (I) Treatment of biaryl-ether derivatives containing a cyano group with NtbOH, followed by treatment with a carbonyl transfer reagent provides tire desired compounds.
  • R 1 , R 3 , R 4 , and R D are as defined for the compound of formula (I).
  • Scheme 6 shows the synthesis of certain compounds of formula (I).
  • Treatment of biaryl-ether derivatives containing a cyano group with NH2OH, followed by treatment with a carbonyl transfer reagent and hydrolysis provides the desired compounds.
  • R 1 , R 3 , R 4 , and R 3 are as defined for the compound of formula (I); and G is a suitable protecting group.
  • Scheme 7 shows the synthesis of certain compounds of fonnula (I).
  • enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered.
  • a racemate may be separated using chiral High Perfonnance Liquid
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or aicoholates are formed when the solvent is alcohol .
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • compositions of any of the compounds detailed herein are embraced by this invention.
  • the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • phrases according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound compri sing the majority of the composition or a salt thereof.
  • a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound or a salt thereof.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity.
  • a composition of substantially pure compound or a salt thereof wherein the composition contains or no more than 3% impurity .
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity in yet other variations, a composition of substantially pure compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1 % impurity, which impurity may be the compound in a different stereochemical form.
  • a composition of substantially pure (S) compound means that the composition contains no more than 13% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
  • the compounds herein are synthetic compounds prepared for administration to an individual such as a human.
  • compositions are provided containing a compound in substantially pure form.
  • the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient.
  • methods of administering a compound are provided .
  • the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • the compound may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water- in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices),
  • One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Fonnulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), winch is incorporated herein by reference.
  • Compounds as described herein may be administered to individuals (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • Examples of earners, which may be used for the preparation of such compositions are lactose, com starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-weting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds described herein can be formulated in a tablet in any dosage form described.
  • compositions comprising a compound provided herein are also described.
  • the composition comprises a compound and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • TOR beta agonizing thyroid hormone receptor beta
  • a method of treating a disorder, which is mediated by TOR beta, in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound pro vided herein, or a therapeutically effective amount of a composition provided herein.
  • Me thods of treating a disorder mediated by TOR beta including without limitation non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and symptoms and
  • a method of agonizing thyroid hormone receptor beta comprising contacting either an effective amount of a compound provided herein, or a salt thereof, such as a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with the TOR beta.
  • a method of selectively agonizing TOR beta over TOR alpha comprising contacting either an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with the TOR beta.
  • the method selectively agonizes TOR beta over TOR alpha by at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold.
  • selectivity is assessed via a biochemical assay, such as the TR-FRET assay described in Example Bl.
  • provided herein is a method of treating a disease or disorder that is mediated by THR beta in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • the disease or disorder is a liver disease or disorder.
  • a method of treating a disease or disorder of the liver associated with sub-optimal TOR beta agonism in a patient in need thereof comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound selectively agonizes TOR beta over THR alpha.
  • provided herein is a method of treating non-alcoholic fatty liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • NASH non-alcoholic steatohepatitis
  • provided herein is a method of treating metabolic syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a method of treating dyslipidemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a method of treating hypertriglyceridemia in a patient need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • provided herein is a method of treating hypercholesterolemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a patient having a disease or disorder associated with THR beta agonism may include, but is not limited to, a patient with an underlying hypothyroid disorder.
  • a method of delaying the onset and/or development of a disease or disorder that is mediated by THR beta in a patient (such as a human) who is at risk for developing the disease or disorder in a patient (such as a human) who is at risk for developing the disease or disorder. It is appreciated that delayed development may encompass prevention in the event the individual does not develop the disease or disorder.
  • An individual at risk of developing a disease or disorder that is mediated by TOR beta in one aspect has one or more risk factors for developing the disease or disorder, such as age, increased waist circumference, high body to mass index or the presence of an associated comorbidity.
  • provided herein is a method of delaying the onset and/or development of non-alcoholic fatty liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a method of delaying the onset and/or development of non-alcoholic steatohepatitis (NASH) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • NASH non-alcoholic steatohepatitis
  • provided herein is a method of delaying the onset and/or development of metabolic syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a method of delaying the onset and/or development of dyslipidemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • provided herein is a method of delaying the onset and/or development of hypertriglyceridemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a method of delaying the onset and/or development of hypercholesterolemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
  • a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non-alcoholic fatty liver disease.
  • a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non alcoholic steatohepatitis (NASH).
  • NASH non alcoholic steatohepatitis
  • a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof for use in tire manufacture of a medicament for the treatment of non-alcoholic fatty- liver disease.
  • a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of non alcoholic steatohepatitis (NASH).
  • NASH non alcoholic steatohepatitis
  • the medicament is for the treatment of dyslipidemia.
  • the medicament is for the treatment of hypertriglyceridemia.
  • the medicament is for the treatment of dyslipidemia.
  • the medicament is for the treatment of hypercholesterolemia.
  • the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.
  • the dose of a compound described herein, or a stereoisomer, tautomer, solvate, or salt thereof, administered to an individual may vary with the particular compound or salt thereof, the method of administration, and the particular disease or disorder, such as non alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), metabolic syndrome, hypertriglyceridemia, dyslipidemia, or hypercholesterolemia, being treated.
  • the amount of the compound, or a stereoisomer, tautomer, solvate, or salt thereof is a therapeutically effective amount.
  • Hie compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdennal.
  • the effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
  • Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery , the pharmacokinetics of the agen t, the severity and course of the disease to be treated , the subject's health status, condition, and weight.
  • An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient.
  • a compound or composition provided herein may he administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g. , twice or three times daily.
  • the dosing frequency can also be intennittent, including a "drug holiday’ (e.g. , once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • the present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein m suitable packaging.
  • the article of manufacture is for use in any of the methods described herein.
  • Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • kits for carrying out the methods of the present disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein or pharmaceutically acceptable salt thereof
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • kits may be in unit dosage forms, bulk packages (e.g. , multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from N, O, and S, wherein the heterocycle is optionally substituted with 1-2 C1-C3 alkyl or C3-C4 cycloalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
  • R 1 is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro; C3-C5 cycloalkyl, CON(R ]0 )2, or NR t0 C()
  • R 2 is H or C1-C3 alkyl
  • L is O, CEE, S, SO, SO2, CO, CHF, CF 2 , C(R U )CN, CHR ! ! , or C(R i ! )R u , wherein each R n is C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R u groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring; each of R 3 and R 4 is independently Cl, Br, Me, or ethyl;
  • R 5 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl, or R 5 together with R 4 and the intervening atoms form a 5-7 membered cycioalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
  • X is absent (i.e., X is a bond), or is O, NR 12 , C(Q)NR i2 , N R ' ( (() ⁇ . C R ' R OCR ’R
  • each R 12 independently is H or methyl.
  • Embodiment 2 The compound of embodiment 1 of formula (IIA), (IIB), (TIIA), (IIIB), (IRC), (IV A), (IVB), (IVC), (IV A), (VB), (VC), (VIA), (VIB), or (VIC):
  • Embodiment 3 The compound of embodiment 1 , of formula (VIIA), (VIIIA), (VIIIB), or (VIIIC):
  • Embodiment 4 Tlie compound of embodiment 1, wherein R 1 is isopropyl.
  • Embodiment 5 The compound of embodiment 1, wherein R 2 is H.
  • Embodiment 6 The compound of embodiment 1 , wherein R 3 is chloro.
  • Embodiment 7 The compound of embodiment 1, wherein R 4 is chloro.
  • Embodiment 8 Idle compound of embodiment 1, wherein R 5 is hydrogen.
  • Embodiment 9 The compound of embodiment 1, wherein X is a bond.
  • Embodiment 10 The compound of embodiment 1, wherein X is CHR 11 , OCHR 11 ,
  • Embodiment 11 The compound of embodiment 1 , wherein X is NH, CH2, OCH2,
  • Embodiment 12 The compound of embodiment 1, wherein -X- is -NH-CH2-, - NHC(O)- or -O-CH2-.
  • Embodiment 13 The compound of embodiment 1, wherein -L- is O.
  • Embodiment 14 A compound selected from those tabulated in Table 1.
  • Embodiment 15 A pharmaceutical composition comprising a compound of embodiment 1 and at least one pharmaceutically acceptable excipient.
  • Embodiment 16 A method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting either an effective amount of a compound of embodiment 1, or an effective amount of the composition of embodiment 15, with the THR beta.
  • THR beta thyroid hormone receptor beta
  • Embodiment 17 A method of treating a disorder, which is mediated by TOR beta, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of embodiment 1, or a therapeutically effective amount of the composition of embodiment 15.
  • the mixture was stirred at 120°C for 6 hours. LCMS showed the starting material was consumed completely and desired MS was detected.
  • the reaction mixture was concentrated under reduced pressure to remove AcOH.
  • the solid was dissolved in water and the pH was adjusted to 9 with saturate NaHCCb solution (10 mL). Then the mixture as partitioned with ethyl acetate (30 mL * 2) andHiO (30 mL). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous NazSOr, filtered and concentrated in vacuum.
  • the solid was diluted in ethyl acetate (10 mL), and then petroleum ether (50 mL) was added in the mixture by portions. The mixture was filtered to collect solid.
  • Example 3 PI and P2: 3-(l-((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-l,2,4-oxadiazol-5(4H)-one
  • 6-(4-bromo-2,6-dichSorophenoxy)-4-isopropylpyridazin-3(2H)-one (6h).
  • a mixture of 6-(4-bromo-2,6-dichloro-phenoxy)-3-chloro-4-isopropyl-pyridazine (6a) (1 g, 2.52 mmol) and NaOAc (827.59 mg, 10.09 mmol) in AcOH (10 mL) was stirred at 120°C for 18 hours. LCMS showed the starting material was consumed completely and the desired MS was found. The mixture was concentrated in vacuum. The solid was dissolved in water and the pH was adjusted to 9 with saturated NaHCOi (2 mL).
  • 6-(2,6-didi!oro-4-hydroxyphenoxy)-4-isopropyl-2-methySpyridazin ⁇ 3(2H) ⁇ one (6d).
  • Example 7 S-(3,5-dichIero-4-((5-isoprGpyl-l-meihyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoxazol-3(2H)-one
  • N'-hydroxy-4-((5-isopropyl-l -methyl-6-oxo-l,6-dihydropyridazin-3yl)oxy)benzimidaniide (25 mg, 67.35 umol) in THF (3 mL) was added DSC (22.43 mg, 87.55 umol) and TEA (13.63 mg, 134.69 umol, 18 75 uL). The mixture was stirred at 60°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was concentrated in vacuum to give a residue.
  • Example 12 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)-2-methylphenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one
  • Example 15 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3- yl)methyl)phenyl)amino)methyl)-l,2,4-oxadiazoI-5(4H)-one
  • Example 16 3-(((3,5-dkhloro-4-((5-isoprGpy!-l-meihyt-6-oxG-l,6-dihydropyridazm-3- yl)methyS)phenyi)am!no)methyi) ⁇ l ,2,4-oxadiazol-5(4H)-one
  • Example 17 N-(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
  • Example 18 3-(((3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazine-3 ⁇
  • acetonitrile (18a) (53 mg, 139.75 umol) in THF (3 mL) was added DMAP (17.07 mg, 139.75 umol) and B0C2O (274 51 mg, 1.26 mmol, 288 95 uL). The mixture was stirred at 25°C for 5 minutes. The mixture was partitioned between ethyl acetate (10 mL*2) and H 2 0 (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous NaiSOr, filtered and concentrated in vacuum to give a residue.
  • Hie residue was purified by prep-TLC (S1O2, petroleum ether : ethyl acetate ::: 1 : 1) to give 19k.
  • Example 20 N-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)suIfonyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
  • Hie residue was purified by Prep-HPLC (aqueous acetonitrile w/ TFA) to give Example 20.
  • reaction mixture was diluted with saturated NaHC03 (5 mL) and extracted with DCM (10 mL * 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue.
  • Example 22 was checked by HPLC and purified by prep-HPLC (column: Waters Abridge 150*25 5u; mobile phase: [water (lOmM NH4HC03)-ACN] ; B%: 5%-35%, 14 min) to give Example 22 as a white solid.
  • Example 24 N-(6-chloro-7-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazm-3-yl)oxy)- 2,3-dihydro-lH-inden-4-yI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carboxamide
  • Example 24 To a solution of 24d (10 mg, 29.96 umol, 1 eq) THF (5 mL) was added TEA (9.09 mg, 89.87 umol, 12.51 uL) and 5-oxo-4H-l,2,4-oxadiazole-3 -carbonyl chloride (4e) (6.67 mg, 44.94 umol). Tire mixture was stirred at 25°C for 0.5 hours. Tire reaction mixture was quenched by addition MeOH (1 mL) at 25 °C, and then concentrated under reduced pressure to give a residue.
  • 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)- one (26a).
  • 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl- pyridazin-3-one (le) (20 g, 60.94 mmol) in CLLCN (200 rriL) and THF (60 mL) under a nitrogen atmosphere was added NaHCOi (15.36 g, 182.82 mmol).
  • Select F 21.59 g, 60.94 mmol
  • Hie mixture was diluted with 1M HC1 to modified pH 6-7 and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with brine 150 mL, dried over anhydrous NarSOi, filtered to give a light yellow liquid The light yellow liquid was concentrated under reduced pressure to remove solvent and until the solid was dissolved out. The mixture was stirred at 20°C for 1 hour and filtered to give Example 26.
  • Hie mixture was stirred at 80°C for 1 hour.
  • Hie reaction mixture was concentrated under reduced pressure to remove DMF.
  • the residue was partitioned between ethyl acetate 10 mL and H2O 5 ml. twice.
  • the combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSOr, filtered and concentrated in vacuum.
  • MS mass calculated for [M+l] + (C21H26CI2FN5O5) required m/z 518.4, LCMS found m/z 518.0.
  • tert-butyl (3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)methyl)carbamate (27d).
  • Example 28 N-(4-((5-(tert-butyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-3,5- diehlorophenyl)-5-o o-4,S-dihydro-l,2,4-oxadiazole-3-carboxamide
  • Example 29 N-(3,5-dichloro-4-((5-(l-hydroxyethyl)-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-cartaoxamide
  • Example 29 The N-(3,5-dichloro-4- ((5-(l-hydroxyethyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazole-3-carboxamide (Example 29) was checked and purified by Chiral SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase: [0.1%NH3*H2O MeOH]; B%: 40%-40%, 10mm) to give Example 29-PI and Example 29-P2.
  • Example 29-P2 MS mass calculated for [M+l]+( C15H11 C12N506) required m/z 428.0, LCMS found m/z 427 9; 1 1 N R (400 MHz, DMSO-de) d 12.26 (s, !H), 10 74 (br s,

Abstract

Provided herein are compounds, preferably thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by THR beta.

Description

THYROID HORMONE RECEPTOR BETA AGONIST COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 62/722,312, filed August 24, 2018, and U.S. Provisional Application No. 62/867,117, filed June 26, 2019, the disclosures of each of which are hereby incorporated by reference in their entireties for all purposes.
FIELD OF THE INVENTION
[0002] This invention relates to compounds, preferably thyroid hormone receptor beta (TOR beta) agonist compounds, compositions thereof, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by TOR beta.
STATE OF THE ART
[0003] Hie beneficial effects arising from treating hyperthyroid or hypothyroid patients with T3 / T4 endogenous ligands or early analogs of these endogenous ligands have been described the literature (Richardson Hill Jr., S. et al. J Clin. Invest. 1960, 39, 523-533). These early studies, as well as similar follow-up studies, established the heart as a major organ for the manifestation of side effects of both hyperthyroidism and hypothyroidism (Klein, 1. et al.
Circulation, 2007, 1725-1735). In particular, tachycardia, hypertrophism, atrial dysrhythmias, and atrial fibrillation are serious concerns. In addition, increased bone turn-over leading to decreased bone mineral density has also been noted. Negative effects at both sites, heart and bone, have been linked to the agonism of the TH R alpha isoform, whereas the beneficial effects of THR agonism in the liver are largely linked to the THR beta isoform (Sinha, R. A. et al. Nat. Rev. Endocrinology 2018, 14, 259-269).
[0004] Diseases or disorders associated with THR beta include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty' liver disease (NAFLD), metabolic syndrome, dyshpidemia, hypertriglyceridemia, and hypercholesterolemia. There is a need for thyroid hormone analogs, such as those that are THR beta agonists, and preferably those that avoid the undesirable effects of hyperthyroidism and hypothyroidism, and maintain the beneficial effects of thyroid hormones, e.g., for the treatment for patients with non-alcoholic steatohepatitis (NASH) in particular, there is a need to develop new thyroid hormone analogs that are selective agonists for THR beta, and preferably those that avoid the undesirable effects associated with agonism of THR alpha, and maintain the beneficial effects of thyroid hormones, e.g., for the treatment for patients with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia.
Figure imgf000003_0001
[QQ05] In one aspect, provided herein is a compound of formula (I):
Figure imgf000003_0002
or a pharmaceutically acceptable salt thereof, wherein:
ring A together with the carbonyl (keto) group within the ring fonn a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting ofN, O, and S, wherein the heterocycle is optionally substituted with 1-2 Ci-C-3 alkyl or C3-C4 cycloalkyl groups, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
R1 is C1-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups, C3-C5 cycloalkyl, CON (R10)2, or NR10CQR10;
R2 is H or Ci-C3 alkyl;
L is O, CT-fc, S, SO, SO2, CO, CHF, CF2, O R )C\. CHR11, or C(R] ])RU;
R3 and R4 are independently Cl, Br, methyl, or ethyl;
3 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl;
or R5 together with R4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
X is absent, O, NRi2, C(0)NR12, NRi2C(G), CR12R12, 0( R ’R CRi2RI2Q, NR12CR12R12, CRi2R!2NR12, SO2NR12, or \R -'SO ·:
each R10 is independently C1-C3 alkyl or H;
each R11 is independently C1-C2 alkyl optionally substituted with 1-5 halo, or two R11 groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring; and
each R12 is independently H or methyl.
In some embodiments, the compound is of formula (IIA) or (PB):
Figure imgf000004_0001
wherein R1, R2, R3, R4, R3, X, and L are as defined for the compound of formula (I).
[QQ07] In some embodiments, the compound is of formula (VD):
Figure imgf000004_0002
w'herein R1, R2, R3, R4, and R5 are as defined in claim 1.
[QQ08] In some embodiments, R1 is C1-C4 alkyl optionally substituted with 1-2 halo or hydroxyl groups, or C3-C5 cycloalkyl. In some embodiments, R1 is isopropyl, t-butyl,
cyclopropyl, or
Figure imgf000004_0003
[0009] In some embodiments, R2 is H or -CH3.
[0010] In some embodiments, R3 is chloro or -CH3. [QQI 1] In some embodiments, R4 is chloro or -CIT; or R5 together with R4 and the intervening atoms form a 5-6 membered cycloalkyl. In some embodiments, R3 together with R4 and the intervening atoms form cyclopentyl. In some embodiments, R5 is H or fluoro.
[0012] In some embodiments, X is a bond. In some embodiments, X is NR!2C(0), OCR12R12, or NR12CR12R12; and each R12 is independently H or methyl. In some embodiments, X is
Figure imgf000005_0001
[0013] In some embodiments, L is O, CH2, SO2, CO, CHR11, or C(Rn)Rn; and each R1 1 is independently methyl or ethyl. In some embodiments, L is O, CHb, SO2, or CO.
[0014] In some embodiments, provided herein is a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
[0015] In one aspect, provided herein is a pharmaceutical composition comprising a compound provided herein and at least one pharmaceutically acceptable excipient.
[0016] In one aspect, provided herein is a method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting either an effective amount of a compound provided herein, or an effective amount of a pharmaceutical composition provided herein, with the THR beta.
[0017] In one aspect, provided herein is a method of treating a disorder which is mediated by THR beta in a patient, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH).
DETAILED DESCRIPTION
Definitions
[0018] As used herein, the following definitions shall apply unless otherwise indicated.
Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.
[QQ19] ‘"Comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding others “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of’ shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention. [QQ20] “Effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in an intended result as desired based on the disclosure herein. Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., and without limitation, by determining the LDso (the dose lethal to 50 % of the population) and the EDso (the dose therapeutically effective in 50 % of the population).
[0021] The term“excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the tenn excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral
administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;
coatings include, e.g., cellulose acetate phthaiate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc =“directly compressible”), honey dc, lactose (anhydrate or monohydrate;
optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl furnarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystailine cellulose, etc.
[0022] “Patient” refers to mammals and includes humans and non-human mammals.
Examples of patients include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.
[QQ23] “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.
[0024] “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt.
3 [QQ25] “Prodrug” refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property. A prodrug, relative to the drug, is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered. A prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). A prodrug may be synthesized using reactants oilier than employing the corresponding drug. For illustration and without limitation, prodrags include, carboxy esters, linear and cyclic phosphate esters and phosphoramide and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates where the hydroxy group is part of an aryl or heteroaryl moiety, where the aryl and heteroaryl may be optionally substituted), and the likes.
[0026] “Salt” refers to an ionic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NHg Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functionality, such salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
[0027] “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a patient. The results may require multiple doses of the compound or the composition.
[0028] “Treating” or“treatment” of a disease in a patient refers to 1) preventing die disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease. As used herein,“treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient. Also encompassed by‘'treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment.
[0029] An“isotopomer” of a compound is a compound m winch one or more atoms of the compound have been replaced with isotopes of those same atoms. For example, where H has been replaced by D or T, or !2C has been replaced by ! 1C or i4N has been replaced by !5N. For example, and without limitation, replacement of with D can in some instances lead to reduced rates of metabolism and therefore longer half-lives. Replacement of H with T can provide radioligands potentially useful in binding studies. Replacement of i2C with the short-lived isotope nC can provide ligands useful in Positron Emission Tomography (PET) scanning. Replacement of i4N with i5N provides compounds that can be detected/monitored by 15N NMR spectroscopy. For example, an isotopomer of a compound containing -CH2CH3 is that compound but containing -CD2CD3 instead of the -CH2CH3.
[0030] Unless a specific isotope of an element is indicated in a formula, the disclosure includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (where H can be 2H, i.e., D). Isotopologues can have isotopic replacements at any or at all locations in a structure, or can have atoms present in natural abundance at any or all locations in a structure.
[0031] “Stereoisomer” or“stereoisomers” refer to compounds that differ in the stereogenicity of the constituent atoms such as, without limitation, in the chirality of one or more stereocenters or related to the cis or trans configuration of a carbon-carbon or carbon-nitrogen double bond. Stereoisomers include enantiomers and diastereomers.
[0032] “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N~ moiety such as pyrazoles, imidazoles, benzimidazoles, triazoies, and tetrazoles.
[QQ33] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyi groups having from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, and more preferably from 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyi groups such as methyl (□¾-), ethyl (CH3CH2-), «-propyl (CH3CH2CH2-), isopropyl ((CH ^CH-), «-butyl (CH3CH2CH2CH2-), isobutyl ((CH^CHCHz-), sec-butyl ((CHsXCH ft CH-), i-butyl (((‘1 Md.'-) «-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((Cl 1 tyC Ci 1 -). Cx alkyl refers to an alkyl group having x number of carbon atoms.
[0034] "Alkenyl" refers to straight or branched monovalent hydrocarbyi groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, ally!, and but-3-en-l-yl. Included within this term are the cis and trims isomers or mixtures of these isomers. Cx alkenyl refers to an alkenyl group having x number of carbon atoms.
[0035] "Alkynyl" refers to straight or branched monovalent hydrocarbyi groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-0=0) unsaturation. Examples of such alkynyl groups include acetylenyl (-CºCH), and propargyl (-CH C^CH). Cx alkynyl refers to an alkynyl group having x number of carbon atoms.
[0036] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aeyioxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonyl amino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryioxy, arylthio, substituted arylthio, arylamino, substituted arydamino, heteroarylammo, substituted heteroarylamino, eycloalkyiamino, substituted cycloalkylamino,
heterocyc!oa!kylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, (carboxyl ester)ammo, (carboxyl esterjoxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkyithio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroaryithio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclyithio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein. [QQ37] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyioxy, ammo, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminotliiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted aiylamino, heteroarylamino, substituted heteroarylamino, cycioaikylamino, substituted cycloaikylammo,
heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, (carboxyl esteriammo, (carboxyl esterjoxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidine, substituted guanidine, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryl oxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclyithio, nitro, SOiH, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.
[0038] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyioxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminotliiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy7, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycioaikylamino, substituted cycioaikylamino,
heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylammo, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to an acetylenic carbon atom. [QQ39] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, f-butoxy, xeobutoxy, and o-pentoxy.
[0040] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein. Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
[0041] "Acyl" refers to the groups 1 !-( (())-. alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl -C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Acyl includes the“acetyl” group CHbCiO)-
[0042] "Acylamino" refers to the groups -NR3uC(0)alkyl, -NR30C(O)substituted
alkyl, -NR30C(())cycloaikyl, -NR30C(O)substituted cycloalkyl, -N
R30C(O)alkenyl, -NR30C(Q)substituted alkenyl, alkoxy, substituted
alkoxy-NR30C(O)alkynyl, -NR30C(O)substituted alkynyl, -NR30C(O)aryl, -NR30C(O)substituted aiyl, -NR30C(O)heteroaryl, -NR30C(O)substituted heteroaryl, -NR30C(O)heterocyciic, and -NR30C(O)substituted heterocyclic wherein R30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, and, substituted aryl, heteroaiyd, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0043] "Acyloxy" refers to the groups alkyl-C(0)0-, substituted alkyl~C(Q)Q-,
alkenyl -C(0)0~, substituted alkenyi-C(0)0-, alkynyl-C(0)0-, substituted alkynyl-C(O)i)-, aryl-C(0)0-, substituted aryl-C(0)0-, cycioaikyl~C(Q)Q~, substituted cycloalkyl-C(0)0-, heteroaryl-C(0)0-, substituted heteroar d-C(G)0~, heterocyclic-C(0)0-, and substituted heterocyc3ic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaiyd, heterocyclic, and substituted heterocyclic are as defined herein.
[0044] “Amino” refers to the group -\! i \ [QQ45] “Substituted amino” refers to the group -NR31R32 where R3 1 and R32 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, aryl, substituted and, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkyiamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, sulfonylamino, and substituted sulfonyl and wherein R3! and R32 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R31 and R32 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein . When R31 is hydrogen and R32 is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R3 ! and R32 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R3i or R32 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R31 nor R32 are hydrogen
[QQ46] "Aminocarbonyl" refers to the group -C(0)NR33R34 where R33 and R34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0047] “Aminothiocarbonyl” refers to the group -C(S)NR33R34 where R33 and R34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted and, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[QQ48] “Aminocarbonylamino” refers to the group -NR30C(O)NR33R34 where R30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalky], or substituted cycloalky], and R33 and R34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0049] “Aminothiocarbonylamino” refers to the group -NR30C(S)NR33R34 where R30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R33 and R34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0050] “Aminocarbonyloxy” refers to the group -0-C(0)NR33R34 where R33 and R34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. [0051] “Aminosulfonyl” refers to the group -S02NR33R34 where R33 and R34 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, aryl, substituted and, cycloalkyl, substituted cycloalkyl, heteroaryi, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, and, substituted and, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0052] “Aminosulfonyloxy” refers to the group -0-S02NR33R34 where R33 and R34 are independently selected from the group consisting of hydrogen , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, a ryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted aikynyi, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryi, substituted heteroaryi, heterocyclic and substituted heterocyclic are as defined herein.
[0053] “Aminosulfonylamino” refers to the group -NR30-SO2NR33R34 where R30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryi, substituted heteroaryi, cycloalkyi, or substituted cycloalkyi, and R33 and RJ4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and w'here R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryi, substituted heteroaryi, heterocyclic and substituted heterocyclic are as defined herein.
[QQ54] “Amidino” refers to the group ~C(=NR3S)NR33R34 where R33, R34, and R35 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0055] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g, phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
[0056] “Substituted aryl” refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryioxy, arylthio, substituted arylthio, arylaniino, substituted aryiamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino,
heterocycloalkylamino, substituted heterocyclylamino carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidmo, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroaryithio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocycly!oxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[0057] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
[0058] "Substituted aryloxy" refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
[QQ59] “Arylthio” refers to the group -S-aryl, where aryl is as defined herein.
[0060] “Substituted arylthio” refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
[0061] “Arylamino” refers to the group -NR3 '(aryl), where aryl is as defined herein and R37 is hydrogen, alkyl, or substituted alkyl. [QQ62] “Substituted arylamino” refers to the group -NR37(substituted aryl), where R37 is hydrogen, alkyl, or substituted alkyl where substituted aryl is as defined herein.
[QQ63] “Carbonyl” refers to the divalent group -C(O)- which is equivalent to -C(=0)-.
[0064] “Carboxy” or“carboxyl” refers to -COOH or salts thereof.
[0065] “Carboxyl ester” or“carboxy ester” refers to the groups -C(0)0-alkyl,
-C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted cycloalkyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl,
-C(0)0-heterocyclic, and -C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0066] “(Carboxyl ester)amino” refers to the group -NR30-C(O)O-alkyl,
-NR30-C(O)O-substituted alkyl, -NR30-C(O)O-alkenyl, -NR30-C(O)O-substituted alkenyl, -NR30-C(O)O-alkynyl, -NR30-C(O)O-substituted alkynyl, -NR30-C(O)O-aryl,
-NR30-C(O)O-substituted and, -NR30-C(O)O-cycloalky], -NR30-C(O)O~substituted cycloalkyl, -NR30-C(O)O-heteroaryd, -NR30-C(O)O-substituted heteroaryl, -NR30-C(O)O-heterocyclic, and -NR30-C(O)O-substituted heterocyclic wherein RJ0 is alkyl or hy drogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0067] “(Carboxyl ester)oxy” refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted alkyl, -0-C(0)0~alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0~alkyny!,
-0-C(0)0-substituted alkynyl, -0-C(0)0-aryd, -0-C(0)0-substituted aiyl,
-0-C(0)0-cycloalkyl, -0-C(0)0-substituted cycloalkyl, -0-C(0)0-heteroaryl,
-0-C(0)-substituted heteroaryl, ~0~C(Q)0~heterocyciic, and -0-C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0068] “Cyano” refers to the group -CºN.
[0069] "Cycloalkyl" refers to saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms, having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Cx cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more the rings can be aryl, heteroaryl, or heterocyclic pro vided that the point of atachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring. "Substituted eycloalkyi" refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acy!oxy, am o, substituted amino, aminocarbonyl, aminotliioearbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)a ino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidine, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heteroeyciyithio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[QQ70] “Cycloalkyloxy” refers to -O-cycloalkyl.
[0071] “Substituted cycloalkyloxy” refers to -0-(substituted cycloalkyl).
[0072] “Cycloalkylamino” refers to the group -NR37(cycloalkyl) where R37 is hydrogen, alkyl, or substituted alkyl.
[0073] “Substituted cycloalkylamino” refers to the group -NR37(substituted cycloalkyl) where R37 is hydrogen, alkyl, or substituted alkyl and substituted cycloalkyl is as defined herein.
[0074] “Cycloalkylthio” refers to -S-cycloalkyl.
[0075] “Substituted cycloalkylthio” refers to -S-(substituted cycloalkyl).
[0076] “Guanidino” refers to the group -NHC(=NH)NH2.
[0077] “Substituted guanidino” refers to ~NR36C(=NR36)N(R36) . where each R36 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R36 groups attached to a common guanidino nitrogen atom are optionally joined toge ther with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R36 is not hydrogen, and wherein said substituents are as defined herein. [QQ78] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
[QQ79] ‘"Hydroxy” or“hydroxyl” refers to the group -OH.
[0080] “Heteroalkylene” refers to an alkylene group wherein one or more carbons is replaced with -0-, -S-, SO ·. -N R0-.
Figure imgf000018_0001
moieties where R° is H or Ci-Ce alkyl. “Substituted heteroalkylene” refers to heteroalkynylene groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.
[0081] "Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g. , indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N 0), sulfinyl, or sulfonyl moieties. Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include 9 or 10 membered heteroaryls, such as indolyl, qu ohnyl, quinolonyl, isoquinolinyl, and isoquinolonyl.
[0082] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
[0083] “Heteroaryloxy” refers to -O-heteroaryl.
[0084] “Substituted heteroaryloxy” refers to the group -O -(substituted heteroaryl).
[0085] “Heteroarylthio” refers to the group -S-heteroaryl .
[0086] “Substituted heteroarylthio” refers to the group -S-(substituted heteroaryl).
[0087] “Heteroarylamino” refers to the group -NR37(heteroaryl) where R3 7 is hydrogen, alkyl, or substituted alkyl .
[0088] “Substituted heteroarylamino” refers to the group -NR37(substituted heteroaryl), where R37 is hydrogen, alkyl, or substituted alkyl and substituted heteroaryl is defined as herein. [QQ89] "Heterocycle" or "heterocyclic" or“heterocycloalkyl” or“heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, and from 1 to 4 ring heteroatoms, preferably from 1 to 3 heteroatoms, and more preferably from 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen Cx
heterocycloalkyl refers to a heterocycloalkyl group having x number of ring atoms including the ring heteroatoms. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N -oxide, sulfmyi, sulfonyl moieties.
[0090] “Heterocyciylene” refers to a divalent saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. “Substituted heterocyciylene” refers to heterocyciylene groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl
[0091] "Substituted heterocyclic" or“substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
[0092] “Heterocyclyloxy” refers to the group -O-heterocycyl.
[0093] “Substituted heterocyclyloxy” refers to the group -0-(substituted heterocycyl).
[0094] “Heterocyclylthio” refers to the group -S-heterocyey!.
[0095] “Substituted heterocyclylthio” refers to the group -S-(substituted heterocycyl).
[0096] “Heterocyclylamino” refers to the group -NR37(heterocyclyl) where R37 is hydrogen, alkyl, or substituted alkyl.
[0097] “Substituted heterocyclylamino” refers to the group -NR37(substituted heterocyclyl), where R37 is hydrogen, alkyl, or substituted alkyl and substituted heterocyclyl is defined as herein.
[0098] Examples of heterocyclyl and heteroaryl include, but are not limited to, azetidinyl, pyrrolyl, imidazo!yl, pyrazoly!, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl, phthaiazinyi, naphthylpyridmyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carboimyl, phenanthridinyl, acridinyl, phenanthrolinyi, isothiazoiyl, phenazinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, imidazolidinyl, miidazolinyl, piperidmyl, piperazinyi, indohnyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinoliny], 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazoly!, thiazolidinyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also referred to as
thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrcolidinyl, and tetrahydrofuranyl.
[0099] “Nitro” refers to the group -NO2.
[0100] Oxo refers to the atom (=0) or (O).
[0101] “Spiro ring systems” refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
[0102] “Sulfinyi” refers to the divalent group -S(O)- or -S(=G)-.
[0103] “Sulfonyl” refers to the divalent group ~S(0)2~ or -S(=0)2-.
[0104] “Substituted sulfonyl” refers to the group -SCh-alkyl, -SC -substituted
alkyl, -SO2-QH, -S02-alkenyl, -S02-substituted alkenyl, -SG2-cycloalkyl, -S02-substituted cylcoalky], -SQr-aryl, -SCh-substituted aryl, -SC -heteroaxyl, -S02-substituted
heteroaryl, -SC -heterocyclic, -SOz-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-SC -, phenyl-SC -, and -rnethylphenyl-SO . Preferred substituted alkyl groups on the substituted alkyl-SCh- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyi, difluromethyl, fluoromethyl and the like.
[0105] “Substituted sulfinyi” refers to the group -SO-alkyl, -SO-substituted
alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SQ-cycloalkyi, -SO-substituted
cylcoalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted
heteroaryl, -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfinyi includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyi, difluromethyl, fluoromethyl and the like.
[0106] “Sulfonyloxy” or“substituted suifonyioxy” refers to the
group -OSO?.-alkyl, -OSOz-substituted alkyl, -OSO2-OH, -OSO -alkenyl, -OS02-substituted alkenyl, -OS 02-cycloalkyl, -OS02-substituted cylcoalkyl, -OS02-aryl, -OS02-substituted aryl, -OS02-heteroaryl, -OS02-substituted heteroaryl, -OSOi-heterocyclic, -OSOi-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted and, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0107] “Sulfonylamino” refers to the group -NR37( substituted sulfonyl) where R57 is hydrogen, alkyl, or substituted alkyl and substituted sulfonyl is as defined here.
[0108] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-,
cycloalkyl C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-,
heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted
heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0109] "Mercapto" or“thiol” refers to the group -SH.
[0110] “Formyl” refers to the group -C(0)H.
[0111] “Thiocarbonyl” refers to the divalent group -C(S)- which is equivalent to -C(=S)-.
[0112] “Thione” refers to the atom (=S)
[0113] "Alky!thio" refers to the group -S-a!kyl wherein alkyl is as defined herein.
[0114] "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyi and the like.
[0115] “Vinyl” refers to unsaturated hydrocarbon radical— CH=CH2, derived from ethylene.
[0116] The terms“optional” or“optionally” as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example,“the nitrogen atom is optionally oxidized to provide for the N-oxide (N 0) moiety” means that the nitrogen atom may but need not be oxidized, and the description includes situations where the nitrogen atom is not oxidized and situations where the nitrogen atom is oxidized.
[OUT] The tenn“optionally substituted” refers to a substituted or unsubstituted group. The substituted group may be substituted with one or more substituents, such as e.g., 1 , 2, 3, 4 or 5 substituents. Preferably, the substituents are selected from the functional groups provided herein. In certain more preferred embodiments, the substituents are selected from oxo, halo, -CN, NCh, -CO2R100, -OR100, -SR100, -SOR100, -SQ2R100, -NRi01R102, ~CONR10iR102,
-SO2NR!0!R102, Ci-Ce alkyl, Ci-Ce alkoxy, -CR!00=C(Ri00)2, -CCR100, C3-C10 cycloalkyl, C4-C10 heterocyclyl, Ce-Ci aryl and C5-C12 heteroaryl, wherein each R100 independently is hydrogen or Ci-Cs alkyl; C3-C12 cycloalkyl; Cr-C 10 heterocyclyl; Ce-C 14 aryl; or C2-C12 heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 halo, 1- 3 CI-CG alkyl, 1-3 CI-CG haloalkyl or 1-3 Ci-G> alkoxy groups. More preferably, the substituents are selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3 and -OCHF2.
[0118] R101 and R102 independently are hydrogen; C;-Cs alkyl, optionally substituted with
-CO2H or an ester thereof, Ci-G> alkoxy, oxo, -CR103=C(Ri03)2, -CCR, C3-C10 cycloalkyl, C3-C10 heterocyclyl, Ce-Ci aryl, or C2-C12 heteroaryl, wherein each RI ( independently is hydrogen or CI-CK alkyl; C3-Ci2 cycioalkyl; C4-Cio heterocyclyl; Ce-Cwaryl; or C2-C] 2 heteroaryl;
wherein each cycioalkyl, heterocyclyl, ar Ί, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R!ul and R102 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
[0119] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality' followed by the adjacent functionality toward the point of attachment. For example, the substituent
“aikoxycarbonylalkyl” refers to the group (alkoxy )-C(0)-(alkyl)-.
[0120] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.
[0121] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 4 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
[0122] It is appreciated that certain features of tire invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every' combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifi cally embraced by the present invention and are disclosed herein just as if each and ever ' such sub-combination of chemical groups w7as individually and explicitly disclosed herein
[0123] In one aspect, provided herein is a compound of formula (I):
Figure imgf000023_0001
or a tautomer or an N -oxide thereof, or an isotopo er of each thereof, or a prodrag of each of the above, or a stereoisomer of tire aforesaid, or a pharmaceutically acceptable salt of each of the foregoing, or a solvate of each of tire preceding, wherein: ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, wdierein the heterocyle is optionally substituted with 1-2 substituents selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
R1 is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro, or hydroxyl groups; C3-C5 cycloalkyl, CON(Rl0)2, or NR]llCORt0, wherein each R!0 is
independently Ci-C3 alkyl or H;
R2 is H or C1-C3 alkyl;
L is O, P 1 -. S, SO, SO2, CO, CHF, CF2, C(Rn)CN such as C(Me)CN, CHR11, or ( (R )R . wherein each Rn is C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R11 groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring; each of R3 and R4 is independently Cl, Br, Me, or ethyl;
R3 is H, halo, C1-C4 alkyl preferably Ctb, or C3-C4 cycloalkyl, or R5 together with R4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1- 2 ring heteroatoms; and
X is absent (i.e., X is a bond), or is O, NR12, C(Q)NR!2, NRi2C(Q), CRi2R12, OCRi2R12,
CR R '(). \ R ‘( R 'R: \ CR12R12NR12, SO2NR12, or NR12S02, wherein each R12 is
independently H or methyl.
[0124] In some embodiments, the compound of fonnula (I) is a pharmaceutically acceptable salt thereof.
[0125] In one embodiment, the compound of formula (1) is a compound of formula (IIA):
Figure imgf000024_0001
wherein the variables are defined as hr formula (I).
[0126] In one embodiment, the compound of formula (1) is a compound of formula (IIB):
Figure imgf000025_0001
wherein the variables are defined as in formula (I)
[0127] In one embodiment, the compound of formula (1) is a compound of formula (IPA).
Figure imgf000025_0002
wherein the variables are defined as in formula (I).
[0128] In one embodiment, the compound of formula (1) is a compound of formula (MB):
Figure imgf000025_0003
(IIIB)
wherein the variables are defined as in formula (I).
[0129] In one embodiment, the compound of formula (I) is a compound of formula (IIIC):
Figure imgf000026_0001
wherein the variables are defined as in formula (I).
[0130] In one embodiment, the compound of formula (I) is a compound of formula (HID):
Figure imgf000026_0002
wherein the variables are defined as in formula (I).
[0131] In one embodiment, the compound of formula (I) is a compound of formula (IV A):
Figure imgf000027_0001
wherein the variables are defined as in formula (I).
[0132] In one embodiment, the compound of formula (I) is a compound of fonnula (IVB):
Figure imgf000027_0002
wherein the variables are defined as in formula (I).
[0133] In one embodiment, the compound of formula (I) is a compound of fonnula (IV C):
Figure imgf000027_0003
(IVC)
wherein the variables are defined as in formula (I).
[0134] In one embodiment, the compound of formula (I) is a compound of formula (IVD):
Figure imgf000028_0001
wherein the variables are defined as in formula (I)
[0135] In one embodiment, the compound of formula (I) is a compound of formula (VA):
Figure imgf000028_0002
wherein the variables are defined as in formula (I).
[0136] In one embodiment, the compound of formula (I) is a compound of formula (VB):
Figure imgf000029_0001
wherein the variables are defined as in formula (I)
[0137] In one embodiment, the compound of formula (I) is a compound of formula (VC):
Figure imgf000029_0002
wherein the variables are defined as in formula (I).
[0138] In one embodiment, the compound of formula (I) is a compound of formula (VD):
Figure imgf000029_0003
(VD)
wherein the variables are defined as in formula (I).
[0139] In one embodiment, the compound of formula (I) is a compound of formula (VIA):
Figure imgf000030_0001
wherein the variables are defined as in formula (I).
[0140] In one embodiment, the compound of formula (I) is a compound of formula (VIB):
Figure imgf000030_0002
wherein the variables are defined as in formula (I).
[0141] In one embodiment, the compound of formula (I) is a compound of formula (VIC):
Figure imgf000031_0001
wherein the variables are defined as in formula (I)
[0142] In one embodiment, the compound of formula (I) is a compound of formula (VID):
Figure imgf000031_0002
wherein the variables are defined as in formula (I)
[0143] In one embodiment, the compound of formula (I) is a compound of formula (VIIA).
Figure imgf000031_0003
(VIIA)
wherein R2 is H or methyl, and the variables are defined as in formula (1).
[0144] In one embodiment, the compound of formula (I) is a compound of formula (VHB):
Figure imgf000032_0001
wherein R2 is H or methyl, and the variables are defined as in formula (I).
[0145] In one embodiment, the compound of formula (I) is a compound of formula (VIIC):
Figure imgf000032_0002
wherein R2 is H or methyl, and the variables are defined as in formula (I).
[0146] In one embodiment, the compound of formula (I) is a compound of formula (VIID):
Figure imgf000033_0001
wherein R2 is H or methyl, and the variables are defined as in formula (I).
[0147] In one embodiment, the compound of fonnula (I) is a compound of formula (VIIIA):
Figure imgf000033_0002
wherein R2 is H or methyl, and the variables are defined as in formula (I).
[0148] In one embodiment, the compound of formula (I) is a compound of formula (VIIIB):
Figure imgf000033_0003
(VIIIB) wherein R2 is H or methyl, and the variables are defined as in formula (1).
[0149] In one embodiment, the compound of formula (I) is a compound of formula (VH!C):
Figure imgf000034_0001
(VfflC) wherein R2 is H or methyl, and the variables are defined as in formula (I).
[0150] In one embodiment, the compound of fonnula (I) is a compound of formula (VIIID):
Figure imgf000034_0002
(VIIID) wherein R2 is H or methyl, and the variables are defined as in formula (I)
[0151] In one embodiment, the compound of formula (I) is a compound of fonnula (IXA), (IXB), (IXC), (IXD), (IXE), or (IXF):
Figure imgf000035_0001
wherein the variables are defined as in formula (I) In some embodiments, the compound is of formula (IXA). In some embodiments, the compound is of formula (IXB). In some embodiments, the compound is of formula (1XC). In some embodiments, the compound is of formula (IXD). In some embodiments, the compound is of formula (IXE). In some embodiments, the compound is of fonnula (IXF).
[0152] In one embodiment, ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein the keto group is not adjacent to the atom attached to X. In one embodiment, ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyle is substituted with 1-2 C1-C3 alkyl or C3-C4 cycloalkyl, and wherein the keto group is not adjacent to the atom attached to X In one embodiment, the 5 membered heterocycle contains 1 -3 ring heteroatoms selected from the group consisting of N and O. In some embodiments, ring A together with the carbonyl (keto) group within the ring is
some embodiments, ring A together with the carbonyl (keto) group within the ring
Figure imgf000036_0001
[0153] In one embodiment, R1 is C1-C4 alkyl. In some embodiments, R1 is methyl, ethyl, n- propyl, isopropyl, «-butyl, or t-butyl. In some embodiments, R1 is C3-C4 alkyl. In one embodiment, R! is isopropyl. In some embodiments, R! is t-butyl. In one embodiment, R1 is C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro. In some embodiments, R! is C1-C4 alkyl optionally substituted with 1-2 halo, such as fluoro or chloro. In one embodiment, R! is Ci - alkyl optionally substituted with 1-5 halo or hydroxyl groups. In some
embodiments, R! is C2-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups. In some embodiments, R1 is C1-C4 alkyl optionally substituted with 1 -2 halo or hydroxyl groups.
In one embodiment, R1 is C1-C4 alkyl optionally substituted with 1 -5 hydroxyl groups. In some embodiments, R! is Ci-C4 alkyl optionally substituted with 1-2 hydroxyl groups. In some embodiments, R1 is C1-C4 alkyl substituted with 1 hydroxyl group. In some embodiments, R1 is C1-C4 alkyl optionally substituted with 1-2 halo or hydroxyl groups. In some embodiments, R! is HO-CH(CH3)-. In some embodiments, R1 is HO-CH(CH2CH3)-. In some embodiments, R1 is H0-C(CH3}2 . In some embodiments, R! is HO-CH2CH(CH3)-. In one embodiment, R1 is C3- Cs cycloalkyl. In some embodiments, R! is a monocyclic C3-C5 cycloalkyl. In some embodiments, R’! is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R] is cyclopropyl. In some embodiments, R! is a fused bicyclic C3-C5 cycloalkyl. In some embodiments, R1 is a bridged bicyclic C3-C5 cycloalkyl.
Figure imgf000036_0003
some embodiments. R1 is
Figure imgf000036_0002
In one embodiment, R1 is CON(R10)2. In one embodiment, R1 is NR10CQR10.
[0154] In one embodiment, each R10 is independently C1-C3 alkyl. In some embodiments, each R10 is independently methyl, ethyl, «-propyl, or isopropyl. In some embodiments, each R10 is methyl. In one embodiment, each R!0 is H. In some embodiments, one R10 is H and the other Ri0 is C1-C3 alkyl. In some embodiments, one R10 is H and the other R10 is methyl. [0155] In one embodiment, R2 is H. In one embodiment, R2 is C1-C3 alkyl. In some embodiments, R2 is methyl, ethyl, «-propyl, or isopropyl. In some embodiments, R2 is methyl. In some embodiments, R2 is H or -CH3.
[0156] In one embodiment, L is O. In one embodiment, L is CH2. In one embodiment, L is S. In one embodiment, L is SO. In one embodiment, L is SO2. In one embodiment, L is CO. In one embodiment, L is CHF. In one embodiment, L is CF2. In one embodiment, L is C(Rn)CN. In one embodiment, L is C(Me)CN. In one embodiment, L is CHR!1 or C(Ru)Rn, wherein each R11 is independently C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R11 groups together with the carbon atom they are attached to fonn a cyclopropyl or cyclobutyl ring. In one embodiment, L is CHR!1. In one embodiment, L is C(RI !)Rn. hi one embodiment, each R11 independently is C1-C2 alkyl, i.e., is methyl or ethyl. In one embodiment, each Ru independently is C1-C2 alkyl substituted with 1 -5 halo, preferably fluoro. In one embodiment, the 2 Ru groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring. In some embodiments, L is O, CH2, SO2, CO, CHR!!, or C(RU)R!1, and each R!1 is independently methyl or ethyl. In some embodiments, L is O, CH2, SO2, or CO.
[0157] In one embodiment, R3 is Cl. In one embodiment, R3 is Br. In one embodiment, R3 is Me. In one embodiment, R3 is ethyl. In some embodiments, R3 is Cl or -CH3. In one embodiment, R4 is Cl. In one embodiment, R4 is Br. In one embodiment, R4 is Me. In one embodiment, R4 is ethyl. In one embodiment, R3 and R4 are each Cl. In some embodiments, R3 and R4 are each methyl. In some embodiments, R3 is Cl and R4 is methyl. In some
embodiments, R3 is methyl and R4 is Cl.
[0158] In one embodiment, R3 is H. In one embodiment, R3 is halo. In some embodiments,
R5 is fluoro, ch!oro, or bromo. In some embodiments, R5 is fluoro. In one embodiment, R5 is C1-C4 alkyl. In some embodiments, R5 is C1-C3 alkyl. In some embodiments, R5 is methyl, ethyl, «-propyl, or isopropyl. In one embodiment, R5 is CH3. In some embodiments, R3 is H or -CH3. In one embodiment, R5 is C.3-C4 cycloalkyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is cyclobutyl. In one embodiment, R4 together with R5 and the intervening atoms form a 5-7 membered cycloalkyl. In some embodiments, R4 together with R3 and the intervening atoms form cyclopentyl or cyclohexyl. In some embodiments, R4 together with R5 and the intervening atoms form cyclopentyl. In one embodiment, R4 together with R5 and the intervening atoms form a 5-7 membered heterocycle containing 1-2 ring heteroatoms. Preferred heteroatoms include one or more of N, O, and S.
[0159] In one embodiment, X is absent (i.e., X is a bond). In one embodiment, X is O. In one embodiment, X is NR12. In one embodiment, X is C(0)NR] 2. In one embodiment, X is NRi2C(0). In one embodiment, X is NRi2S02. In one embodiment, X is SO2NR12. In one embodiment, X is NR12C(0). In one embodiment, X is CRi2R!2. In one embodiment, X is QCRi2R12. In one embodiment, X is CR12Ri2Q. In one embodiment, X is CR!2Ri2NH. In one embodiment, X is NR12CR12R!2. In some embodiments, X is NR!2C(0), QCR!2R12, or NR!2CRi2R12, and each R12 is independently H or methyl. In some embodiments, X is N(CH3)CH2. In one embodiment, X is CR12Ri2NR]2 In one embodiment, X is NH. In one embodiment, X is CH2. In one embodiment, X is OCtb. In one embodiment, X is CH2O. In one embodiment, X is NHCH2. In one embodiment, X is CH2NH. In one embodiment, X is NHC(O). In one embodiment, X is C(0)NH. In one embodiment, X is SO2NH. In one embodiment, X is NHSO2. In some embodiments, X is OCH2, NHCH2, NHC(O), N(CH3)CH2, or N{1 1)0 !((.'! 1 · } . In one embodiment, R!2 is H. In one embodiment, R!2 is methyl. In some embodiments, all R12 groups in a given moiety, such as OCRi2R!2, are H. In some
embodiments, all R12 groups in a given moiety, such as OCRl2R12, are methyl. In some embodiments, the R12 groups in a given moiety, such as QCR12Ri2, are a combination of H and methyl.
[0160] In one aspect, provided is a compound of formula (I) wherein the compound has any one or more of the following features:
(I) ring A together with the carbonyl group within the ring is:
Figure imgf000038_0001
(iii) C1-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups; or
(iv) C3-C3 cycloalkyl;
(HI) R2 is H or C1-C3 alkyl;
(IV) RJ is Cl or methyl; (V) R4 is Cl or methyl;
(VI) R5 is H, halo, or Ci-Cr alkyl;
(VII) R5 together with R4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
(Mil) X is:
(v) a bond; or
(vi) NR12C(0), OCR12R12, or NR12CR12R12, wherein each R12 is independently H or methyl; and
(IX) L is O, CH2, SC , or CO.
[0161] In one variation, (I) applies. In one variation, (II) applies. In one variation, (III) applies. In one variation, (IV) applies. In one variation, (V) applies. In one variation, (VI) applies. In one variation, (VII) applies. In one variation, (VIII) applies. In one variation, (IX) applies. In one aspect of this variation, (I), (II), (III), (IV), (V), (VI), (VIII), and (IX) apply. In another aspect of this variation, (I), (II), (III), (IV), (VII), (VIII), and (IX) apply. In one variation, (i), (iii), and (vi) apply. In one variation, (ii), (iii), and (v) apply. In one variation, (i), (in), and (vi) apply. In one variation, (i), (iv), and (vi) apply. In one variation, (1), (iii), (VII), and (vi) apply.
[0162] In some embodiments, the compound of formula (I) is an agonist of THR beta. In some embodiments, the compound of formula (I) is an agonist of TOR beta and is selective over TOR alpha. In some embodiments, the compound of formula (I) has at least 2-fold selectivity for TOR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 5 -fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 10-fold selectivity for TOR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 20-fold selectivity for THR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 50-fold selectivity for THR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 75 -fold selectivity for THR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 100-fold selectivity for TOR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold selectivity for TOR beta over THR alpha. In any such embodiment, in one aspect selectivity is assessed via a biochemical assay, such as the TR-FRET assay described in Example B 1.
[0163] In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment or aspect pro vided herein with respect to the ring A moiety of formula (1) may be combined with every description, variation, embodiment or aspect of R1, R2, R3, R4, R5, Ri0, R! i, Ri2, X, and L the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for ail formulae. For example, all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to any of formulae as detailed herein, such as formulae (IIA), (IIB), (PίA)-(ΪPO), (IVA)-(rVD), (VA)-(VD), (ViA)-(ViD), (VIIA)- (VIID), (VIITA)-(VTIID), and (IXA)-(IXF), and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae.
[0164] In some embodiments, provided is a compound selected from the compounds in Table 1, or pharmaceutically acceptable salt thereof. Although certain compounds described in the present disclosure, including in Table 1, are presented as specific stereoisomers and/or in a non stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1, are herein described.
[0165] In one embodiment, provided herein is a compound selected from those tabulated below in Table 1 :
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
or a tautomer or an N-oxide thereof, or an isotopomer of each thereof, or a prodrug of each of the above, or a stereoisomer of the aforesaid, or a pharmaceutically acceptable salt of each of the foregoing, or a solvate of each of the preceding.
[0166] In some embodiments, provided herein is a compound selected from those listed in Table 1 or a pharmaceutically acceptable salt thereof.
[0167] The invention also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, prodrags, or isotopomers, of the compounds described. Unless stereochemistry' is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racernic, non-racemic, enantioenriehed and scalemic mixtures of a compound are embraced.
Methods of Synthesis
Scheme 1: General synthesis of biaryl-ether core
ammonium
persulfate
Figure imgf000044_0001
basic conditions
Figure imgf000044_0002
optional N-alkyiation hydrolysis substituent or PG
Figure imgf000044_0004
Figure imgf000044_0003
T = Br, CN, NH;
Figure imgf000044_0005
wherein R1, R3, R4, and R5 are as defined for the compound of formula (I); T is Br, CN, or NHL·; and PG and G are suitable protecting groups.
[0168] The biaryl-ether core of the compounds disclosed herein can be prepared as outlined in Scheme 1. Reaction of 3,6-dichloropyridazine and compounds of general formula R'-CCbH with ammonium persulfate provides R^substituted dichloropyridazine compounds, which can then be reacted with phenol derivatives, hydrolyzed, and optionally N-protected to provide the desired intermediate compounds.
Scheme 1’: Alternative pyridazine synthesis
Figure imgf000045_0004
wherein R1 is as defined for the compound of formula (I).
[0169] Scheme G provides an alternative synthesis of the pyridazines used for the preparation of compounds of fonnula (I) disclosed herein. Reaction of 3,6-dichloro-l,2,4,5-tetrazine with R!-substituted acetylenes affords R! -substituted dichloropyridazine compounds.
Figure imgf000045_0001
Figure imgf000045_0005
N-a!kyiation then
deprotection
Figure imgf000045_0003
Figure imgf000045_0002
wherein R1, R3, R4, and R5 are as defined for the compound of formula (I); and G is a suitable protecting group.
[0170] Scheme la outlines a synthesis wherein G is an alkyl group and T is Nhb. Compounds having the biaryl-ether core with an amine moiety can undergo phthalimide protection, N- alkylation, and subsequent deprotection to provide the desired intermediate compounds.
Scheme 2:
Figure imgf000046_0001
wherein R1, R3, R4, R3, and R1 -' are as defined for the compound of formula (I); and PG, G, and Gi are suitable protecting groups
[0171] Scheme 2 outlines the synthesis of certain compounds of formula (I) disclosed herein. Compounds having the biaryl-ether core with an amine moiety, for example as provided in Scheme la, can undergo N-alkylation and second amine derivatization, followed by reaction with NH2OH, treatment with a carbonyl transfer reagent, and optional deprotection to afford the desired compounds.
Scheme 2a:
Figure imgf000047_0001
Figure imgf000047_0003
wherein R1, R3, R4, R5, and R12 are as defined for the compound of formula (I); and PG and Gi are suitable protecting groups.
[0172] Scheme 2a outlines an alternative synthesis of certain compounds of formula (1) disclosed herein. Compounds having the biaryl-ether core with an amine moiety can undergo N~ alkylation, protection of the amine group, reaction with NH2OH, treatmen t with a carbonyl transfer reagent, and optional deprotection or hydrolysis to afford the desired compounds.
Figure imgf000047_0002
wherein R1, R3, R4, R5, and ring A are as defined for the compound of formula (I); and G and Gi are suitable protecting groups
[0173] Scheme 3 show's the synthesis of certain compounds of formula (I). Reaction of biaryl- ether derivatives containing an amine moiety with carboxylic acid deri vatives of ring A provides amide bond formation to form the desired compounds. Scheme 4:
Figure imgf000048_0002
Figure imgf000048_0003
hydrolysis
wherein R1, R3, R4, R'. and R12 are as defined for the compound of formula (I); and G and PG are suitable protecting groups.
[0174] Scheme 4 shows the synthesis of certain compounds of formula (I). Palladium- mediated hydroxylation of biaryl -ether derivatives containing a bromo group, followed by O- alkylation, reaction with NthOH, treatment with a carbonyl transfer reagent, and optional deprotection or hydrolysis provides the desired compounds.
Scheme 5:
Figure imgf000048_0001
Figure imgf000048_0004
wherein R1, R3, R4, and R5 are as defined for the compound of formula (I); and G is a suitable protecting group. [0175] Scheme 5 shows the synthesis of certain compounds of formula (I) Treatment of biaryl-ether derivatives containing a cyano group with NtbOH, followed by treatment with a carbonyl transfer reagent provides tire desired compounds.
Figure imgf000049_0001
Figure imgf000049_0006
wherein R1, R3, R4, and RD are as defined for the compound of formula (I).
[0176] Scheme 6 shows the synthesis of certain compounds of formula (I). Treatment of biaryl-ether derivatives containing a cyano group with NH2OH, followed by treatment with a carbonyl transfer reagent and hydrolysis provides the desired compounds.
diazotization
Figure imgf000049_0004
iodination
Figure imgf000049_0002
Figure imgf000049_0003
Figure imgf000049_0005
wherein R1, R3, R4, and R3 are as defined for the compound of formula (I); and G is a suitable protecting group.
[0177] Scheme 7 shows the synthesis of certain compounds of fonnula (I).
Diazotization/iodination of biaryl-ether derivatives containing an amino group, followed by Sonogashira coupling, reaction with HbOH. and subsequent optional deprotection provides the desired compounds.
[0178] Synthesis of certain compounds provided herein are schematically illustrated above, and provided in the Examples section below. The variables listed in the schemes above are as defined for the compound of fonnula (!) or any variation, embodiments, or aspect thereof. Synthesis of other compounds provided herein will be apparent to the skilled artisan based on the guidance provided herein and based on synthetic methods well known to the skilled artisan.
[0179] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Perfonnance Liquid
Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
[0180] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
[0181] Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or aicoholates are formed when the solvent is alcohol . Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
[0182] It is understood that the synthetic process disclosed here may be modified to arrive at various compounds of the invention by selection of appropriate reagents and starting materials. It is also understood that where protection of certain active or incompatible groups (e.g., an amine or a carboxylic acid) is required, the formulae in e.g., the scheme(s) provided here intend and include compounds where such active or incompatible groups are in appropriate protected forms. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006.
Pharmaceutical Compositions and Formulations
[0183] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Phannaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
[0184] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In one variation, '‘substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound compri sing the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound or a salt thereof. In one variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity . In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity in yet other variations, a composition of substantially pure compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1 % impurity, which impurity may be the compound in a different stereochemical form. For instance, and without limitation, a composition of substantially pure (S) compound means that the composition contains no more than 13% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
[0185] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual such as a human. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering a compound are provided . The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
[0186] The compound may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water- in-oil liquid emulsions), solutions and elixirs.
[0187] One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Fonnulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), winch is incorporated herein by reference.
[0188] Compounds as described herein may be administered to individuals (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of earners, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-weting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
[0189] Any of the compounds described herein can be formulated in a tablet in any dosage form described.
[QI 90] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided.
Methods of Use/Treatments
[0191] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
[0192] In one aspect, provided herein is a method of agonizing thyroid hormone receptor beta (TOR beta) comprising contacting either an effective amount of a compound provided herein, or an effective amount of a pharmaceutical composition provided herein, with the TOR beta.
[0193] In one aspect, provided herein is a method of treating a disorder, which is mediated by TOR beta, in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound pro vided herein, or a therapeutically effective amount of a composition provided herein. [Q194] Me thods of treating a disorder mediated by TOR beta, including without limitation non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and symptoms and
manifestations of each thereof are well known to the skilled artisan and can be adapted to treating such a disorder with a compound or composition provided herein.
[0195] In one aspect, provided herein is a method of agonizing thyroid hormone receptor beta (TOR beta) comprising contacting either an effective amount of a compound provided herein, or a salt thereof, such as a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with the TOR beta. In one aspect, provided herein is a method of selectively agonizing TOR beta over TOR alpha comprising contacting either an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with the TOR beta. In one such aspect, the method selectively agonizes TOR beta over TOR alpha by at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold. In any such embodiment, in one aspect selectivity is assessed via a biochemical assay, such as the TR-FRET assay described in Example Bl.
[0196] In one aspect, provided herein is a method of treating a disease or disorder that is mediated by THR beta in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, the disease or disorder is a liver disease or disorder. In one aspect, provided herein is a method of treating a disease or disorder of the liver associated with sub-optimal TOR beta agonism in a patient in need thereof, comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound selectively agonizes TOR beta over THR alpha.
[0197] In one aspect, provided herein is a method of treating non-alcoholic fatty liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of treating metabolic syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of treating dyslipidemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of treating hypertriglyceridemia in a patient need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of treating hypercholesterolemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
[0198] In any of the embodiments described herein, a patient having a disease or disorder associated with THR beta agonism may include, but is not limited to, a patient with an underlying hypothyroid disorder.
[0199] In another aspect is provided a method of delaying the onset and/or development of a disease or disorder that is mediated by THR beta in a patient (such as a human) who is at risk for developing the disease or disorder. It is appreciated that delayed development may encompass prevention in the event the individual does not develop the disease or disorder. An individual at risk of developing a disease or disorder that is mediated by TOR beta in one aspect has one or more risk factors for developing the disease or disorder, such as age, increased waist circumference, high body to mass index or the presence of an associated comorbidity.
[0200] In one aspect, provided herein is a method of delaying the onset and/or development of non-alcoholic fatty liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of delaying the onset and/or development of non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of delaying the onset and/or development of metabolic syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of delaying the onset and/or development of dyslipidemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of delaying the onset and/or development of hypertriglyceridemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In one aspect, provided herein is a method of delaying the onset and/or development of hypercholesterolemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
[0201] In one aspect, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for use in therapy. In some embodiments, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non-alcoholic fatty liver disease. In some embodiments, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non alcoholic steatohepatitis (NASH). In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of metabolic syndrome. In some embodiments, provided is a compound of formula (1) or any variation thereof, or a pharmaceutically7 acceptable salt thereof, or a pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of dyslipidemia. In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of hypertriglyceridemia. In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of hypercholesterolemia.
[0202] In another embodiment, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for use in tire manufacture of a medicament for the treatment of non-alcoholic fatty- liver disease. In another embodiment, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of non alcoholic steatohepatitis (NASH). In another embodiment, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of metabolic syndrome. In some embodiments, the medicament is for the treatment of dyslipidemia. In some embodiments, the medicament is for the treatment of hypertriglyceridemia. In some embodiments, the medicament is for the treatment of dyslipidemia. In some embodiments, the medicament is for the treatment of hypercholesterolemia.
[0203] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.
Dosing and Method of Administration
[Q204] The dose of a compound described herein, or a stereoisomer, tautomer, solvate, or salt thereof, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease or disorder, such as non alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), metabolic syndrome, hypertriglyceridemia, dyslipidemia, or hypercholesterolemia, being treated. In some embodiments, the amount of the compound, or a stereoisomer, tautomer, solvate, or salt thereof, is a therapeutically effective amount.
[0205] Hie compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdennal.
[0206] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery , the pharmacokinetics of the agen t, the severity and course of the disease to be treated , the subject's health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
[0207] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient. [Q208] A compound or composition provided herein may he administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g. , twice or three times daily. The dosing frequency can also be intennittent, including a "drug holiday’ (e.g. , once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
Articles of Manufacture and Kits
[0209] The present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein m suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.
[0210] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or pharmaceutically acceptable salt thereof The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of non-alcoholic steatohepatitis (NASH).
[0211] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
[0212] The kits may be in unit dosage forms, bulk packages (e.g. , multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
[0213] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual.
Exemplary Embodiments
[0214] The present disclosure is further described by the following embodiments. The features of each of the embodiments are combinable with any of the other embodiments where appropriate and practical .
[0215] Embodiment !. A compound of formula (I-a):
Figure imgf000059_0001
(I-a)
or a tautomer or an N -oxide thereof, or an isotopomer of each thereof, or a prodrug of each of the above, or a stereoisomer of the aforesaid, or a pharmaceutically acceptable salt of each of the foregoing, or a solvate of each of the preceding, wherein: ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from N, O, and S, wherein the heterocycle is optionally substituted with 1-2 C1-C3 alkyl or C3-C4 cycloalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X; R1 is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro; C3-C5 cycloalkyl, CON(R]0)2, or NRt0C()R10, wherein each Ri0 independently is C1-C3 alkyl or H;
R2 is H or C1-C3 alkyl;
L is O, CEE, S, SO, SO2, CO, CHF, CF2, C(RU)CN, CHR! !, or C(Ri !)Ru, wherein each Rn is C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 Ru groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring; each of R3 and R4 is independently Cl, Br, Me, or ethyl;
R5 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl, or R5 together with R4 and the intervening atoms form a 5-7 membered cycioalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
X is absent (i.e., X is a bond), or is O, NR12, C(Q)NRi2, N R '( (()}. C R 'R OCR ’R
CR! 2R120, NR12CR!2R12, CRi2Rl2NR12, SO2NR12, NR12S02 wherein each R12 independently is H or methyl.
[0216] Embodiment 2. The compound of embodiment 1 of formula (IIA), (IIB), (TIIA), (IIIB), (IRC), (IV A), (IVB), (IVC), (IV A), (VB), (VC), (VIA), (VIB), or (VIC):
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
wherein the variables are defined as in embodiment 1.
[0217] Embodiment 3. The compound of embodiment 1 , of formula (VIIA),
Figure imgf000062_0002
(VIIIA), (VIIIB), or (VIIIC):
Figure imgf000062_0003
(VIIIA) (VIIIB) (VIIIC) wherein R2 is H or methyl, and the remaining variables are defined as in embodiment 1.
[0218] Embodiment 4. Tlie compound of embodiment 1, wherein R1 is isopropyl.
[0219] Embodiment 5. The compound of embodiment 1, wherein R2 is H. [Q220] Embodiment 6. The compound of embodiment 1 , wherein R3 is chloro.
[0221] Embodiment 7. The compound of embodiment 1, wherein R4 is chloro.
[Q222] Embodiment 8. Idle compound of embodiment 1, wherein R5 is hydrogen.
[0223] Embodiment 9. The compound of embodiment 1, wherein X is a bond.
[0224] Embodiment 10. The compound of embodiment 1, wherein X is CHR11, OCHR11,
N R !CHRU, NR ( I I . ( HR NI L CHR1 :NR: !, M IC R R; !, C(0)NR12, NRi2C(0), SO2NR12, or NR S02, wherein R12 is defined as in embodiment 1.
[0225] Embodiment 11. The compound of embodiment 1 , wherein X is NH, CH2, OCH2,
( 1 1 0. NEICEL·, (T I ! !. C(0)NH, NT !('(()). SO2NH, or NHSO2.
[0226] Embodiment 12. The compound of embodiment 1, wherein -X- is -NH-CH2-, - NHC(O)- or -O-CH2-.
[0227] Embodiment 13. The compound of embodiment 1, wherein -L- is O.
[0228] Embodiment 14. A compound selected from those tabulated in Table 1.
[0229] Embodiment 15. A pharmaceutical composition comprising a compound of embodiment 1 and at least one pharmaceutically acceptable excipient.
[0230] Embodiment 16. A method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting either an effective amount of a compound of embodiment 1, or an effective amount of the composition of embodiment 15, with the THR beta.
[0231] Embodiment 17. A method of treating a disorder, which is mediated by TOR beta, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of embodiment 1, or a therapeutically effective amount of the composition of embodiment 15.
Figure imgf000063_0001
[0232] It is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of present disclosure.
[0233] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds of this disclosure are deemed to be within the scope of this disclosure. For example, the synthesis of non -exemplified compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled in the art, e.g., by
appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will he recognized as having applicability for preparing other compounds of the present disclosure. [Q234] The following abbreviations may be relevant for the application.
Abbreviations
Ac: acetyl
ACN : acetonitrile
Boc: tertiarybutyloxycarbonyl
Bu: butyl
DBA: dihenzylideneaeetone
DMAP : dimethylaminopyridine
DMF : dim eth ylformami de
DMF -DMA : dimethylformamide dimethylacetal
DMS O : dimethyl sulfoxide
DSC: disuccinimidylcarbonate
Et: ethyl
Me: methyl
Pr: propyl
Py or Pyr: pyridine
rt: room temperature
SEMC1: 2-(Trimethylsilyl)ethoxymethyl chloride
SFC: supercritical fluid chromatography
TEA: triethylamine
THF: tetrahydrofuran
TFA: trifluoroacetic acid
t-Bu Xphos: 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl Synthetic Examples
Scheme A: 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one
Figure imgf000065_0001
[0235] 3,6-dkhloro-4-isopropyIpyridazine (la). Sulfuric acid (19.75 g, 201.37 mmol, 10.73 mL) was added to a mixture of 3,6-dichloropyridazine (10 g, 67.12 mmol) , 2-methylpropanoic acid (6.21 g, 70.48 mmol, 6.54 mL) and AgN03 (5 70 g, 33 56 mmol, 5.64 mL) in H2O (200 mL) at 60°C. Then a solution of ammonium persulphate (45.95 g, 201.37 mmol) intizO (100 mL) was added by drop-wise to the mixture at 75°C, the resulting mixture was stirred at 75°C for 30min TLC showed the reaction was completed after cooling the mixture was adjusted to pH ::= 9—10 with NH3.H2O, the mixture was extracted with ethyl acetate (200 mL*2), the organic phases were washed with brine (100 mL), dried over NaiSQ-g filtered and concentrated to give la. The product was used directly in next step. MS mass calculated for [M+l]÷ (CrHgChNi) requires m/z 191.1, LCMS found m/z 191.1; Ή NMR (4Q0MHZ, CDCb) d 7.38 (s, 1H), 3.24 - 3.31 (m, I I I). 1.31 (d, J = 6.8 HZ, 61 1).
[0236] 3,S~diehloro-4~((6 Chloro~S-isopropylpyridazm-3-yI)oxy)aniline (lb). To a solution of 4-amino-2,6-d hlorophenol (3 g, 16.85 mmol) and 3,6-dichloro-4~isopropylpyridazme (la) (3.22 g, 16.85 mmol) m DMSO (30 mL) was added K2CO3 (9.32 g, 67.41 mmol) and Cul ( 1.93 g, 10.11 mmol). Then the mixture was degassed and purged with N . for 3 times, and stirred at 90°C for 16 hours under N2 atmosphere. TLC and LCMS showed the starting material was consumed completely and desired MS was detected. Tire mixture was concentrated in vacuum. The residue was partitioned between ethyl acetate (1000 mL*2) andHbO (500 mL). The combined organic phase was washed with brine (50 niL*3), dried with anhydrous NarSOr, filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate = 10: 1 to 3 : 1, according TLC) to give lb. MS mass calculated for [M+l]+ (C13H12CI3N3O) requires m/z 332.0, LCMS found m/z 332.0; !H NMR (400MHZ, DMSO) 6 7.66 (s, 1 1 1}. 6.67 - 6.76 (m, 2H), 5 67 (s, 2H), 3 1 1 - 3 21 (m, 1 1 1). 1.28 (d, J = 6.85 HZ, 6H).
[0237] 2-(3,5-dichloro-4-((5-isopropy!-6-oxo-l,6-dihydropyridazin-3- yI)oxy)phenyl)isomdolme-l,3-dione (lc). To a mixture of 3,5-dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl)oxy)aniline (lb) (2.6 g, 7.82 mmol) and isobenzofuran-l ,3-dione (1 .16 g, 7.82 mmol) iiiHOAc (5 mL) was added NaOAc (3.21 g, 39.08 mmol). The mixture was stirred at 120°C for 6 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solid was dissolved in water and the pH was adjusted to 9 with saturate NaHCCb solution (10 mL). Then the mixture as partitioned with ethyl acetate (30 mL * 2) andHiO (30 mL). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous NazSOr, filtered and concentrated in vacuum. The solid was diluted in ethyl acetate (10 mL), and then petroleum ether (50 mL) was added in the mixture by portions. The mixture was filtered to collect solid. The solid was dried to give lc. MS mass calculated for [M+l]+ (C21H15CI2N3O4) requires m/z 444.0, LCMS found m/z 444.1; ¾ NMR (400MHZ, DMSO) d 12.21 (s, 1H), 7.98 - 8.06 (m, 2H), 7.90 - 7.97 (m, 2H), 7 78 - 7.83 (m, 2H), 7.46 (s, 1H), 3.03 - 3.10 (m, 1 1 1 ). 1.20 (d, J = 6.85 HZ, 61 1 ).
[Q238] 2-(3,5-dichloro-4-((5-isopropyS-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoindoline-l,3-dione (Id). A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo- l,6-dihydropyridazin-3-yl)oxy)phenyl)iso-indoline-l,3-dione (lc) (500 mg, 1.13 mmol) in DMF-DMA (4 mL) was stirred at 110°C for 2.5 hours. TLC showed the starting material was consumed completely and two new spots formed. The mixture was concentrated in vacuum. The residue was partitioned between Ethyl acetate (10 niL*2) andEbO (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSOr, filtered and concentrated in vacuum to give I d. The product was used directly in next step without further purification.
[0239] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H),-one (le).
A mixture of 2-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoindoline- l ,3-dione (I d) (700 mg, 1.53 mmol) and butan-l -amine (335 13 mg, 4.58 mmol) in MeOH ( 10 mL) was stirred at 70°C for 1 hour. TLC (Petroleum ether: Ethyl acetate = 1 : 1, PI : Rr = 0.6) and LCMS showed the starting material was consumed completely and desired MS was detected. Tire mixture was concentrated in vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1 : 1, PI : Rr ::: 0.6) to give le. MS mass calculated for [M+l]+ (C14H15CI2N3O2) requires m/z' 328.1, LCMS found mJz 328.2; 1 1 NMR (400MHZ, ( G)30G)) d 7 22 (s, 1 H) 6.70 (s, 1 H) 3.52 (s, 3 H) 3.17 (dt, ,7=13.81 7.13 Hz, 1 H) 1.43 (s, 2 H) 1 .25 (d, J= 6.58 Hz, 6 H).
Example 1 : 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy}pheny!)amino)methy!)-l ,2,4~oxadiazol-5(4H)~one
Figure imgf000067_0001
[0240] 2 ((3,5-dic Soro~4-((S~isopropyl-l-met yS-6-oxo-l,6 dihydropyridazin-3- yi)oxy}phenyi)ammo)~acetonitriie (If)· To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4- isopropyl-2-methyipyridazin-3(2H)-one (le) (240 mg, 731.28 umol) in ACN (4 mL) was added 2-bromoacetonitrile (438.58 mg, 3.66 mmol, 243.65 uL), Nal (219.23 mg, 1.46 mmol) and K2CQ3 (202.13 mg, 1.46 mmol). Then the mixture was sealed in tube, and stirred at 100°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (5 mL*3). The combined filtrates were concentrated to dryness to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1 : 1, PI : Rf = 0.5) to give If as a yellow oil. MS mass calculated for [M+l]+ (CieHieCbJSiO?.) requires m/z 367.1, LCMS found m/z 366.8: ¾ NMR (400MHZ, CDCb) d 7.04 (s, 1H), 6.72 (s, 2H), 4.13 (d, J = 6.85 HZ, 21 1). 3.54 (s, 3H), 3.21 - 3.28 (m, 1H), 1.26 (d, I = 6 85 HZ, 5H).
[0241] Tert-butyl (cyanomethyl)(3,5-dichIoro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl) oxy)-phenyl)carbamate (Ig). To a solution 2-((3,5-dichloro-4-((5- isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropyri-dazin-3 -yl)oxy)phenyl)amino)acetonitrile (If) (210 mg, 571 85 umol) in THF (3 mL) was added BociO (374.41 mg, 1 .72 mmol, 394.12 uL) and DMAP (69.86 mg, 571.85 umol). The mixture was stirred at 40°C for 3 hours. TLC (Petroleum ether: Ethyl acetate = 1: 1, PI : Rf = 0.9) and LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was partitioned between ethyl acetate (10 mL*2) and H2O (3 mL) twice. Tire combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na2S04, filtered and concentrated in vacuum to give a residue.
The residue was purified by prep-TLC (SiCfe, petroleum ether: ethyl acetate = 3: 1, PI : Rr = 0.5) to give Ig MS mass calculated for [M+l]+ (C21H24CI2N4O4) requires m/z 467.1 , LCMS found m/z 467.0; Ή NMR (400MHZ, CDCb)5 7.45 (s, 2H), 4.61 (s, 2H), 3.43 (s, 3H), 3.13 (dt, I 1 .8. 6.8 HZ, 1H), 1.45 (s, 9H), 1.22 (d, J = 6.8 HZ, 61 1).
[0242] (Z)-tert-fouty! (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-l- methyl-6-oxo-l ,6-dihy-dropyridazin-3-yl)oxy)phenyl)carbamate (l h). To a solution of tert- butyl (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)carbamate (Ig) (250 mg, 534.94 umol) in DMF (3 mL) was added NH2OH.HCI (297.39 mg, 4.28 mmol) and NaOAc (351.06 mg, 4.28 mmol). The mixture was stirred at 80°C for 1 hour. LCMS showed the starting material w¾s consumed completely and desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL*2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSOy filtered and concentrated in vacuum to give Ih (260 mg, crude) as a yellow solid. The product was used directly for the next step without further purification. MS mass calculated for [M+l]+
(C21H27CI2N5O5) requires rn/z 500.1, LCMS found m/z 500.1.
[0243] tert-buty! (3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (li). To a solution of (Z/E)-tert-butyl (2-aniino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-l-methyl-6- oxo-l,6-diliydropyridazin-3-yl)oxy)phenyl)-carbamate (lh) (260 mg, 519.61 urnol) in THF (3 mL) was added DSC (173.04 mg, 675.49 nmol, 1.3 eq) and TEA (105 16 mg, 1 .04 mmol,
144.65 uL). The mixture was stirred at 60°C for 16 hours. TLC (Dichloromethane: Methanol ::: 10: 1 , PI : Rf = 0.3) and LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was partitioned between ethyl acetate (10 mL*2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSOr, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (SiCfe, DCM: MeOH = 10: 1 , PI : Rj = 0.3) to give li. MS mass calculated for [M+If (C22H25CI2N5O6) requires m/z 526.1, LCMS found m/z 526.2; 1 1 NMR (400MHZ, CD30D)5 7.54 (s, 2H), 7.32 (s, IH), 4.77 (s, 2H), 3.48 (s, 3H), 3.18 (dt, J = 13.6, 6.84 HZ, 1H), 1.46 (s, 9H), 1.27 (d, I = 6.8 HZ, 6H).
[0244] 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H),-one (Example 1), To a solution of tert- buty 1 (3 , 5 -dichloro-4-((5-isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropyridazm-3 -yl)oxy)phenyl)((5 - oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (li) (170 mg, 322.97 uniol) in
HCl/EtOAc (2 mL) was stirred at 25°C for 2 hours LCMS andHPLC showed the starting material was consumed completely and desired MS was detected. The mixture was diluted with water (0.5 mL) and tire pH was adjusted to 8 with NaHCCh (5 mL). Then the mixture was partitioned with Ethyl acetate 10 mL twice. The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NarSOr, filtered and concentrated in vacuum to give a residue. The residue was purified by Prep-HPLC (FA) column: Luna C18 100*30 5u; mobile phase: [water (0.2%FA)~ACNJ; B%: 25%~60%,12. min] to give Example 1. MS mass calculated for | M 1 1 ((' : ·! ! : ·( ENT) ,} requires m/z 426.1 , LCMS found m/z 426.0; Ή NMR (400 MHZ, CD30D)5 7.23 (s, IH), 6.76 (s, 21 1 ). 4.88 (s, 139H), 4.28 (s, 21 1 ). 3.50 (s, 3H), 3.12 - 3.21 (m, IH), 1.25 (d, J = 7.06 HZ, 6H). Example 2: 3-(((3,S dic loro-4 ((5-isopropyl~l~methyl-6-oxo-l,6-dihydropyridazin-3- yI}oxy)p enyl}(methyl)am!5io)methy!)-l ,2,4~oxadiazol-5(4H)~one
Figure imgf000070_0001
[0245] 2-((3, 5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l, 6-dihydropyridazin-3- yl)oxy)phenyl)(methyl)amino) acetonitrile (2a). To a solution of 2-((3,5-dichloro-4-((5- isopropyi-l-methyl~6~oxo-i,6-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitri!e (If) (50 mg, 136.15 umol) in THF (2 mL) was added CS2CO3 (66.54 mg, 204.23 umol) and Mel (193.26 rug, 1.36 mmol, 84.76 uL). The mixture was stirred at l00°C for 16 hours under sealed tube. TLC and LCMS showed -30% of Reactant If was remained and the desired MS was detected. The suspension was filtered through a pad of Ce!ite and the pad cake was washed with EtOAc (5 mL*3). The combined filtrates were concentrated to dryness to give a residue. The residue was purified by prep-TLC (SiCfe, petroleum ether: ethyl acetate = 1 : 1, according TLC) to give the 2a. MS mass calculated for [M+l]+( C17H18CI2N4O2) requires mlz 381.1 , LCMS found m/z 381.0
P NMR (400 MHZ, CDCI3) d 7.03 (d, I = 0.7 HZ, 1H), 6.82 (s, 21 1 ). 4.19 (s, 21 1). 3.54 (s, 3H), 3.28 - 3.20 (m, 1H), 3.05 (s, 3H), 1.27 - 1.25 (m, 6H).
[0246] (Z)-2-((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yI)oxy)pheny!)(methy!)-amino)-N'~hydroxyacetimidamide (2b). To a solution of 2-((3,5- dichloro-4-((5 -isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropy ridazin-3 - yl)oxy)phenyl)(methyI)amino)acetonitrile (2a) (52 mg, 136.39 umol) in DMF (2 mL) was added NH2OH.HCI (75.82 mg, 1.09 mmol) and NaOAc (89.51 mg, 1.09 mmol). The mixture was stirred at 80°C for 6 hours. TLC showed reactant 2a was consumed completely, LCMS showed one main peak with desired MS. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (5 mL*3). The combined filtrates were washed with brine (10 mL), dried over anhydrous NaiSCri, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, DCM: MeOH = 10: 1, according TLC) to give 2b. MS mass calculated for [M+l]+( C17H21CI2NSO3) requires m/z 414.1, LCMS found m/z 414.1.
[0247] 3-(((3,5-dichloro-4-((5-isopropyl-l -methyl-6-oxo-l ,6-dihydropyridazin-3- yl)oxy)phenyl)(methyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one (Example 2). To a solution of (Z/E)-2-((3 ,5 -dichloro-4-((5 -isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropyridazm-3 - yl)oxy)phenyl)(methyl)amino)-N'-hydroxyacetimidamide (2b) (30 mg, 65.17 umol) in THF (2 mL) was added DSC (21 .70 mg, 84.72 umol) and TEA (33.97 mg, 335.75 umol, 46.73 uL). The mixture was stirred at 80°C for 2 hours. TLC and LCMS showed 2b was consumed completely and desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was checked by HPLC and then purified by prep-HPLC (column: Waters Atlantis T3 150*30*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 40%-70%, 13min) to give Example 2. MS mass calculated for [M+l]+( C18H19CI2N5O4) requires m/z 440.1, LCMS found m/z 440 1. 1 1 WIR (400MHZ, CD3OD) d 7.24 (s, 1H), 6.92 (s, 31 1). 4.48 (s, 2H), 3.49 (s, 3H), 3.17 (td, J = 7.2, 13.9 HZ, 1H), 3.05 (s, 3H), 1 .26 (d, I = 6 8 HZ, 6H).
Example 3: PI and P2: 3-(l-((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-l,2,4-oxadiazol-5(4H)-one
Figure imgf000072_0001
Exampie 3-P1 Examp!e 3-P2
[Q248] 2-((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)amino) propanenitrile (3a). A mixture of 6-(4-amino-2,6-dichlorophenoxy)-4- isopropyl-2-methylpyridazin-3(2H)-one (le) (0.2 g, 609.40 umol, 1 eq), K2CO3 (168.44 mg,
1.22 mmo), Nal (182.69 mg, 1.22 mmol) and 2-bromopropanenitrile (816 44 mg, 6.09 mmol) in CH3CN (5 mL) was added to a seal tube and heated to 90°C for 16 hours. LCMS showed desired MS and STM of le, the mixture was filtered and washed with ethyl acetate (10 mL*2). The combined filtrates was washed with brine (20 ml,), and the organic phase was concentrated to give 3a (0.25 g, crude), the crude product was used for the next step directly. MS mass calculated for [M+l]+ (C17H18CI2N4O2) requires m/z 381.1, LCMS found rn/z 381.0.
[Q249] Tert-butyl (l-cyanoethyI)(3,5-dichloro-4-((5-isopropyS-l-methyl-6-oxo-l,6- dihydropyridazi ~3~yI)oxy)phenyI}carbaniate (3b). A mixture of 2-((3,5-dichloro-4-((5- isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropyridazin-3-yl)oxy)pheny l)amino) propanenitrile (3a) (0.25 g, 655.73 nmol), B0C2G (429.33 mg, 1.97 mmol, 451.93 uL) and DMAP (80.11 mg, 655.73 umol) in THF (5 mL) was heated to 50°C for 1 hour. LCMS showed desired MS, and TLC showed new spot. The mixture was concentrated, and the residue was purified by prep- TLC (petroleum ether: ethyl acetate = 3: 1) to give 3b. MS mass calculated for [M+ l]+
(C22H26CI2N4O4) requires rn/z 481.1, LCMS found m/z 481.3; 'H NMR (400MHz, CDCb) d 7.31 (s, 2H), 7 07 (s, 1H), 3 51 (s, 3H), 3.30 - 3 23 (m, 1H), 3.20 (q, J= 7 0 Hz, 1H), 2 03 (s, 3H),
1.75 (d, ./ 7 0 Hz, 31 1). 1.57 (s, 4H), 1.51 - 1.43 (m, 9H), 1 28 (d, J= 6.8 Hz, 6H).
[025Q] (Z/E)-tert-butyl (l-amino-l-(hydroxyimioo)propan-2-yS)(3,5 dichIoro-4 ((5- isopropyl-l-methy!-6-oxo-l,6-dihydropyridaz!n-3-yS)oxy)phenyI)carbamate (3c). A mixture of tert-butyl ( 1 -cyanoethyl)(3 ,5 -dichloro-4-((5 -i sopropy] - 1 -methyl-6-oxo- 1 ,6-dihydropyridazin- 3-yl)oxy) phenyl)carbamate (3b) (80 mg, 166.19 umol), NH2OH.HCI (92 39 mg, 1.33 mmol) and NaOAc (109.07 mg, 1 33 mmol) in DMF (3 mL) was heated to 80°C for 5 hours. LCMS showed desired MS, TLC (Petroleum ether: Ethyl acetate = 1 : 1, Rf = 0.47) showed new point, the mixture was filtered and washed with ethyl acetate (10 mL*2), the filtrate was washed with brine (10 mL*2), the organic phase was dried over NaiSCb, filtered and concentrated, the residue was purified by prep-TLC (petroleum ether : ethyl acetate = 1 : 1) to give 3c. MS mass calculated for [M+l]+ (C22H29CI2N5O5) requires m/z 514 2, LCMS found m/z 514.0;
[0251] Tert-butyl (3,5-diehIoro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yI)oxy)phenyl)(l-(S-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yI)ethyI)carbamate (3d). A mixture of (Z/E)-tert-butyl (I -amino-l-(hydroxyimino)propan-2-yl)(3,5-dichloro-4-((5-isopropyl-l- methyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)carbamate (3c) (39 mg, 75.82 umol), DSC (25.25 mg, 98.56 umol) and TEA (15.34 mg, 151.63 umol, 21.11 uL) in THF (4 mL) was heated to 60°C for 2 hours. Then the mixture was heated to reflux for another 4 hours. TLC
(Petroleum ether: Ethyl acetate = 1: 1, Rf = 0) showed the reaction was completed, and the mixture was concentrated to give 3d (70 mg, crude), which was used for the next step directly. MS mass calculated for [M+l]+ (C23H27Q2N5O6) requires m/z 540.1, LCMS found m/z 540.2;
[0252] 3-(l-((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)amino)ethyl)-l ,2,4-oxadiazol-5(4H)-one (Example 3). To a solution of tert- butyl (3 , 5 -dichloro-4-((5-isopropyl- 1 -methyl-6-oxo- 1 ,6-ditiydropyridazin-3 -yl)oxy)phenyl)( 1 - (5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)ethyl)carbamate (3d) (70 mg, 129.53 umol) in DCM (2 mL) was added TEA (0.5 mL), and the mixture was stirred at 25°C for 50 min. LCMS showed the reaction was completed, and desired MS was detected. Then the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) (column: Waters Atlantis T3
150*30*5um; mobile phase: [water (0.225 %FA)-ACN]; B%: 40%-80%, 13min) to give 3-(l- ((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazin-3- yl)oxy)phenyl)ainmo)ethyl)-l ,2,4-oxadiazol-5(4H)-one Example 3. MS mass calculated for i M i G (C18H19CI2N5O4) requires m/z 440.0, LCMS found rn/z 440.1 ; Ή NMR (400MHz, CD3OD) d 7.25 (d, ./ 0.8 Hz, 1H), 6.78 (s, 2H), 4.55 (q, J= 6.8 Hz, 1H), 3.52 (s, 3H), 3.23 - 3.13 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1 27 (d, J= 7.0 Hz, 6H)
[0253] SFC separation: 3-(l -((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l ,6- dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-l,2,4-oxadiazol-5(4H)-one (Example 3) (17.17 mg, 39.00 umo!, 1 eq) was separated by SFC ([Monitoring] Instrument: Thar SFC80 preparative SFC; Column: Chiralpak AS-H, 250*30mm i.d. lOu; Mobile phase: A for CO2 and B for MeOH (0.1% ammonia); Gradient: B%=4Q%; Flow rate:70 g/min; Wavelength: 220 nm; Column temperature: 40°C; System back pressure: 100 bar) to give Example-Pl; MS mass calculated for i M i j (CisHiTCbNoOr) requires m/z 440.1, LCMS found m/z 440.0; Tl NMR (400MHz, CD3OD) d 7.23 (d, J = 0.8 Hz, 1H), 6.75 (s, 2H), 4.48 (q, J = 6.8 Hz, i l l). 3.51 (s, 3H), 3.17 (id. J = 6.6, 13.6 Hz, 1H), 1.58 (d, J = 6.8 Hz, 31 1). 1.26 (d, J = 7.2 Hz, 6H) and Example-P2; MS mass calculated for [M+i]+ (C18H19CI2N5O4) requires m/z 440.1, LCMS found rn/z 440.0; Ή NMR (400MHz, CD3OD) 6 7.23 (s, 1H), 6.75 (s, 2H), 4.48 (q, J = 6.8 Hz, i l l). 3.51 (s, 3H), 3.17 (quin, j = 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 31 1). 1.26 (d, J = 6.8 Hz, 61 1)
Example 4: N-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000074_0001
[Q254] (Z/E)-ethyl 2-amino-2-(hydroxyimino)acetate (4a), To a solution of ethyl carbonocyanidate (2.5 g, 25.23 mmol, 2.48 mL) in EtOH (25 mL) was added NH2OH.HCI (2.63 g, 37.85 mmol) and NaiCO.s (2.67 g, 25.23 mmol). The mixture was stirred at 25°C for 2 hours. TLC showed the reaction was completed. LCMS showed one main peak with desired MS. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (5 mL) and extracted with etOAc (20 mL * 5). The combined organic layers was washed with brine (5 mL), dried over anhydrous NazSQr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by re-crystallization from MTBE: petroleum ether =1 : 1 (20 mL) at 70°C to give 4a. MS mass calculated for [M+l]+ (C4H8N2O3) requires m/z 133.1, LCMS found m/z 133.1; Ή NMR (400MHz, CDCI3) d 8.90 (br s, 1H), 5.12 (br s, 2H), 4 34 (q, j = 7.1 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H)
[0255] (Z)-ethyl 2-amino-2-(((ethoxycarbonyl)oxy)imino)acetate (4b). To a solution of (Z/E)-ethyl 2-amino-2-(hydroxyimino)acetate (4a) (1 g, 7.57 mmol) in DCM (5 mL) was added TEA (2.30 g, 22.71 mmol, 3.16 mL) and ethyl carbonochlondate (903.56 mg, 8.33 mmol,
792.59 uL). The mixture was stirred at 0°C for lhour. TLC indicated 5a was consumed completely and one new spot fonned. Tire reaction was clean according to TLC. The reaction mixture was concentrated under reduce pressure to give 4b (1.34 g, crude). H NMR (400MHz, (TXT) d 5.44 (br s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.42 - 1.38 (m, 31 1). 1.38 - 1.34 (m, 3H).
[0256] Ethyl 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxylate (4c). A solution of (Z/E)- ethyl 2-amino-2-(((ethoxycarbonyl)oxy)imino)acetate (4b) (1.34 g, 6.56 mmol) in AcOH (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120°C for 10 hours under N2 atmosphere. LCMS showed 4b was consumed completely and one main peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH and then to give the 4c (1.03 g, crude). The crude product was used in next step without further purification. MS mass calculated for [M-TJ CsHeNiQ^ requires m/z 157.0, LCMS found m/z 157.0.
[0257] 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxylic add (4d). To a solution of ethyl 5- oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxylate (4c) (200 mg, 1.26 mmol, 1 eq) in MeOH (1 mL) and H2O (0.2 mL) was added LiOH (36 35 mg, 1 .52 mmol, 1.2 eq). The mixture was stirred at 25°C for 1 hour. TLC showed reactant 4 was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduce pressure to give a residue. The residue was diluted with HC3 (1M, 5 mL) to adjust the pH = 4~6 and then extracted with EtOAc (5 mL * 4). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaiSOi, filtered and concentrated under reduced pressure to give 4d (1 14 mg, crude). The crude product was used in next step without further purification. MS mass calculated for [M+l]+ ii.’.-l l.-L .O n requires m/z 159.0, LCMS found no m/z;‘H N MR (400MHz, DMSO) d 4.35 (q, j 7.0 Hz, 2H), 1.28 (t, I = 7 0 Hz, 3H).
[0258] 5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carbonyl chloride (4e). To a solution of 5- oxo-4, 5-dihydro- 1, 2, 4-oxadiazole-3-carhoxylic acid (4d) ( 110 mg, 845.77 umol) in THF (3 mL) was added (COCl)?. (128.82 mg, 1.01 mmol, 88.84 uL) and DMF (6.18 mg, 84.58 umol, 6.51 uL) The mixture was sti rred at 25 °C for 1 hour. A few drops of reaction mixture were quenched with MeOH for monitoring. TLC indicated 4d was consumed completely and one new spot formed, the mixture was concentrated under reduced pressure to give 4e (155 mg, crude). The crude product was used in next step without further purification.
[0259] N-(3,5-dichioro-4-((5-isopropyI-l-methyI-6-oxo-l,6~dihydropyridazin-3 yi)oxy)phenyl)-5-oxo~4,5~dihydro-l, 2,· 4-oxadiazole- 3-carboxamide (Example 4). To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (le) (20 mg, 60.94 umol) in THF (3 ml,) was added TEA (18.50 mg, 182.82 umol, 25.45 uL) and 5-oxo- 4, 5-dihydro- 1 , 2, 4-oxadiazole-3-carhonyl chloride (4e) (13 57 mg, 91 .41 umol). The mixture was stirred at 25°C for 0.5 hour. LCMS showed le was consumed completely and desired MS was detected. The reaction mixture was quenched by addition MeOH (1 mL) at 25 °C, and then concentrated under reduced pressure to give a residue. The residue was checked by HPLC and purified by Prep-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (lOmM NH4HC03)-ACN]; B%: 30%-55%, lOmin) to give Example 4. MS mass calculated for [M+IJA C17H15CI2N5O5) requires m/z 440.0, LCMS found m/z 440.0. ¾ NMR (400MHz, CD3OD) d 7.93 (s, 2H), 7.31 (s, 1H), 3 51 (s, 3 IT), 3.19 (qumd, J = 7.0, 13.8 Hz, 1H), 1 .27 (d, J = 6.8 Hz, 6H).
Example 5: 3-(((3,5-dichIoro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3- yI)oxy)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one
Figure imgf000077_0001
yl)oxy)phenyI)amino)acetonitrile (5a). To a solution of 3,5-dichloro-4-((6-chloro-5- isopropyipyridazin-3-yl)oxy)aniline (lb) (180 mg, 432.94 umol) and 2-bromoacetonitrile (259.65 mg, 2.16 mmol, 144.25 uL) in ACN (2 nit .) was added K2CO3 ( 119.67 mg, 865.87 umol) and Nal (129.79 mg, 865.87 umol). The mixture was stirred at l00°C for 16 hours under sealed tube. LCMS showed reactant 1 b was consumed completely and desired MS was detected. Hie reaction mixture was concentrated under reduce pressure to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 1 : 1, according TLC) to give 4a. MS mass calculated for [M+l]+( C15H13CI3N4O) requires m/z 371 .0, LCMS found rn/z .371.0. Ή NMR (400MHz, CDs Cl) d 7.25 (s, 1H), 6.66 (s, 2H), 4.83 - 4.77 (m, 1H), 4.05 (d, J =
6.4 Hz, 2H), 3.29 (td, J = 6.8, 13.6 Hz, 1H), 1.37 (d, J = 6.8 Hz, 6H).
[0261] Tert-butyi (cyanomethyl)(3,5 dichloro-4 ((6-chSoro-5-isopropyIpyridazin 3- yI)oxy)pheny!)carbamate (5b). To a solution of 2-((3,5-dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl)oxy)phenyl)amino)acetonitrile (5a) (172 mg, 379.50 umol) in THF ( 10 mL) was added DMAP (51.00 mg, 417.45 umol) and B0C2O (248.48 mg, 1.14 mmol, 261.55 uL) The mixture was stirred at 40°C for 2 hours. TLC indicated Reactant 5a was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 1 : 1, according TLC) to give Sb. MS mass calculated for [M+l]+( C20H21CI3N4O3) requires m/z 471.1, LCMS found m/z 471.1. Ή NMR (400MHz, CD3C1) d 7.38 (s, 2H), 7.24 (s, 1H), 4.48 (s, 2H), 3.29 {id. J = 6.7, 13.6 Hz, i l l). 1.53 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H).
[0262] (Z/E)-tert-butyl (2-amino-2-(hydroxyimino)ethyS)(3,5-dichSoro-4-((6~chIoro-5- isepropy!pyridazin-3-yi)oxy)phenyi)carbamate (5c). To a solution of tert-butyl
(cyanomethyl)(3 ,5 -dichloro-4-((6-chloro-5 -isopropylpy ridazin-3 -yi)oxy)phenyi)carbamate (5b) (145 mg, 307.36 umol) in DMF (2 mL) was added NH2.OH.HCl (170.87 mg, 2.46 mmol) and NaOAc (201.70 mg, 2.46 mmol). The mixture was stirred at 80°C for 6 hours. TLC showed reactant 5b was consumed completely. LCMS showed one main peak with desired MS. Hie suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (5 ml*3). The combined filtrates were washed with brine (10 mL), dried over anhydrous NaiSG-i, filtered and concentrated under reduce pressure to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 1 : 1, according TLC) to give 5c. MS mass calculated for [M+l]+(C2oH24CblSl504) requires m/z 504.1, LCMS found m/z 504.1. ‘H NMR (400MHz, CD3CI) d 7.37 (s, 2H), 7.21 (s, i l l). 5.11 (br s, 2H), 4 23 (s, 2H), 3.28 (td, J = 7.0,
13.8 Hz, H I). 2.09 (s, i l l). 1 .49 (s, 9H), 1.36 (d, I = 6 8 Hz, 61 1 ).
[0263] Tert-butyl (3,5-dichIoro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyI)((5- oxo-4, S-dihydro-l,2,4-oxadiazol-3-yI)methyl)carbamaie (5d). To a solution of (Z/E)-tert- butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3- yl)oxy)phenyl)carbamate (5c) (50 mg, 89.15 umol) in THF (2 mL) was added DSC (29.69 mg,
115.89 umol) and TEA (33.97 mg, 335.75 umol, 46.73 uL). Hie mixture was stirred at 80°C for 1 hour. LCMS showed 5c was consumed completely and desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (dichloromethane: methanol = 10: 1, according TLC) to give 5d. MS mass calculated for [M+l]+( C21H22CI3N5O5) requires m/z 530.1, LCMS found m/z 530.1.
[0264] 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one (Example 5). To a solution of (tert- butyl (3 , 5 -dichloro-4-((6-chloro-5 -isopropylpyridazin-3 -yl)oxy)phenyl)((5 -oxo-4,5 -dihy dro- l,2,4-oxadiazol-3-yl)methyl)carbamate) 5d (68 mg, 115.30 umol) in AcOH (3 mL) was added NaOAc (75.66 mg, 922.40 umol). The mixture was stirred at H0°C for 3 hours. LCMS showed reactant 5d was consumed and desired MS was detected. Hie reaction mixture was concentrated under reduced pressure to remove AcOH and then to give a residue. Hie residue -was checked by HPLC and purified by Prep-HPLC (column: Waters Abridge Prep OBD C18 150*30 5u; mobile phase: [water (0.225 %FA)-ACN]; B%: 30%-65%, 13min) to give Example 5. MS mass calculated for [M+l f( CieHisChNsO*) requires m/z 412 0, LCMS found m/z 412.0 ¾ NMR (400MHz, DM SO ) 6 12.11 (s, i l l). 7.31 (s, 1H), 6.79 (s, 21 1 ). 6.66 (br t, J = 6.0 Hz, i l l). 4.27 (d, J = 6.2 Hz, 2H), 3.02 (id, J = 7.0, 13.6 Hz, 1H), 1.17 (d, J = 6.8 Hz, 6H).
Example 6: 3-((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3-
Figure imgf000079_0001
Figure imgf000079_0002
enoxy)-3-chloro-4-isopropyIpyridazine (6a), A mixtun of 4-bromo-2,6-dichloro-phenol (3.04 g, 12.56 mmol) and 3,6-dichloro-4-isopropyl-pyridazine
(la) (2 g, 10.47 mmol) in pyridine (10 mL) was stirred at 130°C for 48 hours in a 100 mL of autoclave. LCMS showed the starting material of la was consumed completely and the desired MS was found. The mixture was diluted with Tol. (30 mL) and concentrated in vacuum. The residue was partitioned between ethyl acetate (30 mL*2) and H2O (10 mL). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous NarSOu filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, petroleum ether: ethyl acetate = 1:0 to 100: 1) to give 6a. MS mass calculated for [M+l]+ (CBHioBrCblNhO) requires m/z 394.9, LCMS found m/z 394.9. 1 1 NMR (400MHz, DMSO) d ppm 7.98 - 8.04 (m,
1 H) 7.92 - 7.97 (m, 1 H) 7.84 (s, 1 H) 3.11 - 3 2.9 (m, 1 H) 1.23 - 1.47 (m, 6 H).
[0266] 6-(4-bromo-2,6-dichSorophenoxy)-4-isopropylpyridazin-3(2H)-one (6h). A mixture of 6-(4-bromo-2,6-dichloro-phenoxy)-3-chloro-4-isopropyl-pyridazine (6a) (1 g, 2.52 mmol) and NaOAc (827.59 mg, 10.09 mmol) in AcOH (10 mL) was stirred at 120°C for 18 hours. LCMS showed the starting material was consumed completely and the desired MS was found. The mixture was concentrated in vacuum. The solid was dissolved in water and the pH was adjusted to 9 with saturated NaHCOi (2 mL). Then the mixture was extracted with Ethyl acetate (10 mL*2). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NazSQy filtered and concentrated in vacuum to give 6b. The product was used directly for the next step without further purification j M+ 1]÷ (Ci 3H1 iBrChNiCh) requires m/z 376.9, LCMS found m/z 376.9. Ή NMR (4G0MHz, DMSO) d ppm 12.22 (br s, 1 H) 7.91 - 8.02 (m, 2 H) 7.39 (s, 1 H) 2.97 - 3.1 1 (m, 1 H) 2.87 - 2.95 (m, 1 H) 1.29 (d, ./ 6.72 Hz, 1 H) 1.15 - 1 2.3 (m, 6 H). [Q267] 6-(4~bromo-2,6-dichlorophenoxy)~4-isopropyl-2-niethyipyridazm-3(2IT)-one (6c).
A mixture of 3-(4-bromo-2,6-dichioro-phenoxy)-5-isopropyl-lH-pyridazin-6-one (6b) (500 mg, 1.32 mmol) in DMF-DMA (22.42 g, 188.19 mmol, 25.00 mL) was stirred at 105°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected.
Hie mixture was concentrated in vacuum. The residue was partitioned between ethyl acetate (10 mL 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSGy filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate=I :Q to 30: 1) to give 6c [M+l]+
(C I Br( L\ ·() · ) requires m/z 391.0, LCMS found m/z 391.0. Ή NMR (400MHz, DMSO) 6 ppm 7.96 (s, 2 H) 7.41 (s, 1 H) 3.32 (s, 1 H) 3.08 (dt, ./ 13.67. 6.84 Hz, 1 H) 2.50 (br d, ./ 3.53 Hz, 8 H) 1.18 (d, .7=7.06 Hz, 5 H) 1.23 (br s, 1 H)
[0268] 6-(2,6-didi!oro-4-hydroxyphenoxy)-4-isopropyl-2-methySpyridazin~3(2H)~one (6d). A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (6c) (170 mg, 433.59 umol), KOH (31.63 mg, 563 67 umol), t-Bu Xphos (27.62 mg, 65.04 umol) and Pd2(dba)3 (39.70 mg, 43 36 umol) in dioxane (8 mL) and H2O (8 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at l00°C for 3.5 hours under N2 atmosphere. TLC showed 6c was consumed completely, and LCMS detected the desired MS. The suspension was filtered through a pad of Ceiite and the pad cake was washed with EtOAc (5 mL*3). Tire combined filtrates were concentrated to give a residue. The residue was purified by prep-TLC (S1O2, ethyl acetate: petroleum ether = 1 : 1 , according TLC) to give 6d. MS mass calculated for j M · ! i ((': il I : iCI ·\ ·() 0 requires m/z 329.0, MS found m/z 329.0. i l l NMR (400MHz, CDCI3) d 7.06 (s, 1H), 6.93 (s, 2H), 6.45 (br s, I I I). 3.55 (s, 31 1). 3.25 (id. J = 6.8,
13.6 Hz, 11 1). 1.27 (d, J = 6.8 Hz, 6H).
[0269] 2-(3,5-dich!oro-4-((5-isopropyl-l~meth S-6-oxo-l ,6~dihydropyridazin-3- yl)oxy)phenoxy)acetonitrile (6e). To a solution of 6-(2,6-dichloro-4-hydroxyphenoxy)-4- isopiOpyl-2-methyipyridazin-3(2H)-one (6d) (40 mg, 121.51 umol) in acetone (2 inL) was added K2CO3 (50.38 mg, 364.54 umol) and 2-bronioacetonitrile (21.86 mg, 182.27 umol, 12.15 uL). The mixture was stirred at 20°C for 2 hours. TLC showed 6d was consumed completely and one new' spot was formed. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH (5 mL*3). The combined filtrates were concentrated to dryness to give a residue. Tire residue was purified by prep-TLC (S1O2, ethyl acetate: petroleum ether = 1 : 1 ) to give 6e as a yellow solid. MS mass calculated for [MM j^Ci&HisChhhCh) requires m/z 368.0, MS found m/z 368.0. ¾ NMR (400MHz, CDC13) d 7.04 (s, 3H), 4.80 (s, 2H), 3.53(s, 3H), 3.25 (id. J = 6.8, 13.4 Hz, 1H), 1.27 (d, J = 6.8 Hz, 61 1 ).
[Q270] (Z/E)-2-(3,5-dichIoro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenoxy)-N'-hydroxyacetimidamide (6f). To a solution of 2-(3,5-dichloro-4-((5- isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropyridazin-3 -yl)oxy)phenoxy)acetonitriie (6e) (38 mg, 103.20 umol) in DMF (2 mL) was added NH20H.HC1 (57.37 mg, 825.61 umol) and NaOAc (67.72 mg, 825.61 umol). Hie mixture was stirred at 80°C for 6 hours. TLC showed 6e was consumed completely, and LCMS showed one main peak with desired MS. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with brine (5 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were dried over anhydrous NaiSOr, filtered and concentrated under reduced pressure to give 6f (66.3 mg, crude). The product was used into the next step without further purification. MS mass calculated for [M+l]+( C16H18CI2N4O4) requires m/z 401.0, LCMS found m/z 401.2.
[0271] 3-((3,5-dichloro-4-((5-isopropyl-l -methyl-6-oxo-l ,6-dihydropyridazin-3- yl)oxy)phenoxy)methyl)-l,2,4-oxadiazol-5(4H)-one (Example 6). To a solution of (Z/E)-2- (3,5 -dichloro-4-((5 -isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropyridazin-3 -yi)oxy)phemoxy)-N'~ hydroxyacetimidamide (6f) (66.3 mg, 132.19 umol) in THF (2 mL) was added DSC (44.02 mg, 171.85 umol) and TEA (26.75 rng, 264.38 umol, 36.80 uL). Hie mixture w'as stirred at 60°C for 4 hours. LCMS showed 6f -was consumed completely and desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*30 5u;mobile phase: [water(0.04%NH3H20)-ACN];B%: 5%~35%, 10min) to give Example 6. MS mass calculated for [M+lfi CnHieChN+Os) requires m/z 427.1, LCMS found m/z 427.1. 'H NMR (400MHz, (1) 4)0) d 7.30 is. 11 1). 7.24 (s, 2H), 5.10 (s, 2H), 3.49 (s, 3H), 3.19 (qumd, J = 7.0, 13.8 Hz, 11 1). 1 27 (d, J = 6.8 Hz, 6H).
Example 7: S-(3,5-dichIero-4-((5-isoprGpyl-l-meihyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoxazol-3(2H)-one
Figure imgf000082_0001
[0272] 6 - { 2 , 6 - d i ch 1 o r o ·· 4 - i o d o p hen ox y ) 4 - i s o p s · o p }4-2 ·· n¾e t h yl p y r i d a z in- 3 (2 H )· o u e (7a). To a solution of 6-(4-ammo-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (le)
(50 mg, 152.35 umol) in HCI (5 M, 304.70 uL) was added NaNC (12.61 mg, 182.82 umol) at 0°C. Then the mixture was stirred for 0.5 hour at 0°C. Then a solution of KI (50.58 mg, 304.70 umol) in HiO (1.5 ml.) was added in the mixture, and the mixture was stirred at 20°C for another 16 hours. TLC indicated Reactant le was consumed completely. LCMS showed Reactant le was consumed completely and one main peak with the desired MS was formed. Hie reaction mixture was extracted with EtOAc (5 mL*4). The combined organic layers were washed with brine (5 ml.), dried over NazSCri, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO , petroleum ether: ethyl acetate::= 1 : 1, product Ri = 0.80, according TLC) to give 7a. MS mass calculated for | M · i j i
C14H12CI2N2O2) requires m/z 438.9, LCMS found m/z 438.9 “H NMR (400MHz, CDC13) d 7.71 (s, 21 1). 7.04 (s, i l l). 3.52 (s, 31 1). 3.25 (td, J = 7.0, 13.4 Hz, 1H), 1.26 (d, J = 6.8 Hz, 61 1).
[Q273] Ethyl 3-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yI)oxy)phenyl)propio!ate (7b). A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2- methy]pyridazm-3(2H)-one (7a) (25 mg, 56.94 umol), ethyl propiolate (12 29 mg, 125.26 umol), PdCPPho hCb. (4.00 mg, 5.69 umol), Cul (2.17 mg, 11.39 umol) and CS2CO3 (37.10 mg, 1 13.88 umol) in THF (5 mL) was degassed and purged with N2 for 3 times. Then the mixture was stirred at 110°C for 0.5 hour under microwave. TLC indicated Reactant 7a was consumed completely and many spots formed. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (5 mL*3). The combined filtrates were concentrated to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 3: 1, according TLC) to give 7b. MS mass calculated for [M+ l]÷( C 19H18CI2N2O4) requires m/z 409.1 , LCMS found m/z 409.1. !H NMR (400MHz, CDCb) d 7.61 (s, 2H), 7.06 (s, 1H), 4.32 (q, J = 7.0 Hz, 2H), 3.51 (s, 3H), 3 25 (quind, J = 6.8, 13.8 Hz, i l l). 1.37 (t, j = 7.2 Hz, 3H), 1.27 (d, J =
6.8 Hz, 6H).
[0274] 5-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoxazol-3(2H)-one (Example 7). To a solution of ethyl 3~(3,5~dicliloro~4-((5~ isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazin-3-y])oxy)pheny])propiolate (7|> (27 mg, 48.56 umol) in MeOH (3 mL) was added NH2OH.HCI (13.50 mg, 194.22 umol) and KOH (16.35 rng, 291.33 umol). The mixture was stirred at 25 °C for 16 hours. TLC showed reactant 7b was consumed completely. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers w¾re washed with brine (5 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was checked by HPLC and purified by prep-HPLC (column: Waters Xbridge Prep OBD C 18 150*30 5u; mobile phase: [water (0.04%NH3H20)-ACN]; B%: 5%-35%, lOmin) to give Example 7. MS mass calculated for [ + 1 ] +( C 1 ?H 15 C 1 zN 3 O 4) requires m/z 396.0, LCMS found m/z 396.0. ¾ NMR (400MHz, CDCb) 6 7.76 (s, 2H), 7.08 (s, 1H), 6.25 (s, i l l}. 3.52 (s, 3H), 3.31 - 3.22 (m, 1H), 1.28 (d, I = 6.8 Hz, 6H).
Example 8: 5-(3,5-dkhIoro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin 3- yl)oxy)phenyl)isoxazol~3(2H)~one
Figure imgf000084_0001
Exampie 8
[0275] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)acetamide (8a). To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-
3-yl)oxy)amime (lb) (1 g, 3.01 mmol) in AcOH (10 mL) was added NaOAc (863.18 mg, 10.52 mmol). The mixture was stirred at l00°C for 16 hours. 5 (MS showed one main peak with the desired MS. Hie reaction mixture was concentrated under reduced pressure to remove AcOH. Hie residue was diluted with vrater (20 mL) and added IN NaOH to adjusted pH = 9-10. The suspension was extracted with EtOAc (10niL*4), the combined organic layers were dried over anhydrous NaiSOr, filtered and concentrated under reduced pressure to give 8a (1.55 g, crude). The product was used into the next step which without further purification MS mass calculated for [M+l]+ (C 15H15Q2N3O3 ) requires m/z 356.1, LCMS found rn/å 356.1.
[Q276] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropySpyridazm-3(2H)-one (8b), To a sol ution of N-(3 ,5 -dich!oro-4-((5 -i sopropyl -6-oxo- 1 ,6-dihydropyridazin~3 - yl)oxy)phenyl)acetamide (8a) ( 1.55 g, 3.48 mmol) in MeOH (20 mL) was added aqueous of NaOH (1 M, 21.26 mL). The mixture was stirred at 120°C for 4 hours. LCMS showed one main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. Hie residue was diluted with water (20 mL) and extracted with EtOAc
(! QmL*4). The combined organic layers vrere dried over anhydrous NaiSO-r, filtered and concentrated under reduce pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate ::: 5: 1 to 1 :5, according TLC) to give 8b.
MS mass calculated for [M+l]+ (C13H13Q2N3O2) requires m/z 314.0, LCMS found m/z 314.0. Ή NMR (400MHz, DMSO) d 12.11 (s. 1 1 1).. 7.25 (s, 1 1 1). 6.64 (s, 2H), 5 60 (s, 21 1). 3.07 - 2 94 (m,
1H), 1.19 - 1.12 (m, 7H).
[0277] 6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazin-3(2H)-one (8c), To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (8b) (250 mg, 795.76 umol) in HC1 (967.1 1 mg, 7.96 mmol, 948.14 uL, 30% purity ) was added NaNCh (65.89 mg, 954.91 umol) at 0°C, the mixture was stirred for 0.5 hour .Then to the mixture was added a solution of KI (264.19 mg, 1.59 mmol) in H?() (5 mL). Then the mixture was stirred at 20°C for another 16 hours. LCMS showed one main peak with the desired MS. The reaction mixture was extracted with EtOAc (10 ml,*4). The combined organic layers were washed, dried over NaiSCri, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCb, petroleum ether: ethyl acetate = 3: 1, product Rr = 0.60, according TLC) to give 8c. MS mass calculated for [M+l]+ (C13H1 1CI2IN2O2) requires m/z 424.9, LCMS found m/z 424.9. Ή NMR (400 MHz, CDCh) d 10.50 - 10.29 (m, 1H), 7.75 - 7.69 (m, 2H), 7.13 - 7.08 (m, 1H), 3.30 - 3.14 (m, 1H), 1.28 - 1.25 (m, 6H).
[Q278] 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-((2-
(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (8d). To a mixture of 6-(2,6-dichloro-4- iodophenoxy)-4-isopropy4pyridazin-3(2H)-one (8c) (50 mg, 117.63 umol), DIPEA (30.41 mg, 235.27 umol, 40.98 uL) in DMF (4 mL) was added 2-(chloromethoxy)etliyl-trimethyl-silane (58.84 mg, 352.90 umol, 62.46 uL). The mixture was degassed and purged with N2 for 3 times, the mixture was stirred at 25°C for 2 hours under N2 atmosphere. TLC indicated 8c was consumed completely. LCMS showed one main peak with the desired MS. The reaction mixture was quenched by addition water (5 mL), and then extracted with EtOAc (6 mL *3). The combined organic layers were concentrated under reduce pressure to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 5: 1, according TLC) to give 8d. MS mass calculated for [M+l]+ (CigHisCiilNiQiSi) requires m/z 555.0, LCMS found m/z 555.0. 1 1 N M R (400 MHz, CD3OD) 6 7.78 - 7 61 (m, 2H), 7.13 - 7.00 (m, 1H), 5.28 - 5.16 (m, 2H), 3.58 - 3.50 (m, 2H), 3.32 - 3.18 (m, 1H), 1.31 - 1 .23 (m, 6H), 0.91 - 0.83 (m, 2H), 0.01 - 0.11 (m, 9H).
[0279] Ethyl 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)- l,6-dihydropyridazin-3-yl)oxy)phenyl)propiolate (8e). A mixture of 6-(2,6-dichloro-4- iodophenoxy)-4-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (8d) (18 mg, 32.41 umol), ethyl propiolate (7 00 mg, 71 .31 umol, 7.00 uL), PdiPPhsLCli (2.28 mg, 3.24 umol), Cul (1.23 mg, 6.48 umol) and CS2CO3 (21.12 mg, 64.83 umol) in THF (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 0.5 hour under microwave. TLC indicated 8d was consumed completely and many spots formed. LCMS showed one main peak with the desired MS was formed. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (5 mL*3). The combined filtrates were concentrated to dryness to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 8: 1, according TLC) to give 8e. MS mass calculated for [M+l]+ (C24H30CI2N2O5 Si) requires m/z 525.1, LCMS found m/z 525.1. Tl NMR (400 MHz, CDsOD) d 7.61 - 7.57 (m, 2H), 7.08 - 7.06 (m, 1H), 5.19 - 5.17 (m, 2H), 4.35 - 4.28 (m, 2H), 3.57 - 3.50 (m, 2H), 3.31 - 3.19 (m, i l l). 1.38 - 1.34 (m, 3H), 1.28 - 1.25 (m, 6H), 0.89 - 0.84 (m, 2H), -0.03 - 0.06 (m, 9H).
[028Q] 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)-l,6- dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (8f). To a solution of Ethyl 3-(3,5- dichloro-4-((5-isopropyl-6-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)-l,6-dihydropyridazin-3- yl)oxy)phenyl)propiolate (8e) (5 mg, 9.51 umol) in MeOH (2 mL) was added NH2OH.HCI (2.64 mg, 38.06 umol) and KOH (3.20 mg, 57.09 umol). Hie mixture was stirred at 25°C for 5 hours. TLC indicated 8e was consumed completely. LCMS showed one main peak with the desired MS was formed. The reaction mixture was concentrated under reduced pressure to remove MeOH. Hie residue was diluted with H2O (5 mL) and extracted with EtOAc (5 mL * 3). Hie combined organic layers were washed with brine (5 mL), dried over anhydrous NazSQy filtered and concentrated under reduce pressure to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 3:2, according TLC) to give 8f. MS mass calculated for i M i G (C’i L Ci‘X >0 -Si) requires m/z 512.1, LCMS found m/z 512.1. 1 1 NMR (400 MHz, CD3OD) d 7.78 - 7.73 (m, 2H), 7.12 - 7.08 (m, 1H), 6.29 - 6.24 (m, 1H), 5.23 - 5.20 (m, 2H), 3.59 - 3.52 (m, 2/H), 3.33 - 3 22 (m, 1H), 1.30 - 1.27 (m, 6H), 0.90 - 0.85 (m, 2H), -0.05 - 0.10 (m, 9H).
[0281] 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoxazol-3(2H)-one (Example 8). A solution of 5-(3,5-dichloro~4~((5-isopropyl~ 6-oxo- l-((2-(trimethylsily])ethoxy)methyl)-l,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol- 3(2H)-one (8f) (4 mg, 7.81 umol) in TFA (2 mL) was stirred at 25°C for 4 hours. LCMS showed 8f was consumed completely and the desired MS was detected. Then the mixture was concentrated in vacuum. The residue was checked by HPLC and purified by prep-HPLC (column: Luna Cl 8 100*30 5u; mobile phase: [water (0.2%FA)-ACN]; B%: 30%-60%, 12min) to give Example 8. MS mass calculated for [M+l]+ (CieHnCbNaOa) requires m/z 382.0, LCMS found m/z 382.0. Ή NMR (400 MHz, CDsOD) d 7.91 - 7.86 (m, 2H), 7.37 - 7.35 (in, 1H), 6.48 - 6.46 (m, H i ). 3.20 - 3.14 (m, i l l). 1.33 - 1.24 (m, 6H).
Example 9: 3-[3,5-dichloro-4-[(5-isopropyl-6-oxo-lH-pyridazin-3-yl)oxy]phenyl]-4H-l,2,4-
Figure imgf000087_0001
[Q282] 3,5-dkMoro~4-(6~cMoro-5-isopropyI-pyridazm-3-yT)oxy~benzonitriIe (9a). A mixture of 3,5-dichloro-4-hydroxy-benzonitrile (la) (100 rng, 531.88 umol) and 3,6-dichloro-4- isopropyl-pyridazine (101.62 mg, 531.88 umol) in Py (3 mL) was stirred at 130°C for 36 hours. LCMS showed la was consumed completely and desired MS was detected. The mixture was diluted with Tol. (5 mL*3) and concentrated in vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 5: 1) to give 9a. MS mass calculated for [M+l]+ (C14H10CI3N3O) requires m/z 342 0, LCMS found m/z 342.1 ; iHNMR (400MHZ, CD3OD) d 8.02 (s, 2H), 7.67 (s, 1H), 3.47 - 3.50 (m, 1H), 3.32 - 3.39 (m, 1H), 1.37 (d, ./ 6.84 HZ, 61 1).
[Q283] (Z/E)-3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-lN'- hydroxybenzimidamide (9b). To a solution of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin- 3-yl)oxy-benzonitrile (9a) (60 mg, 175.13 umol) in DMF (2 mL) was added NH2OH.HCI (97.36 mg, 1.40 mmol) and NaOAc (114.93 mg, 1.40 mmol). The mixture was stirred at 80°C for 1 hour. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL*2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSCL, filtered and concentrated in vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 5: 1) to give 9b. MS mass calculated for [M+l]+
(C14H13 Q3N4O2) requires m/z 375.0, LCMS found m/z 375.0.
[Q284] 3-(3,5-dichloro-4-((6-chloro-5-isopropyIpyridazin-3-yl)oxy)phenyl)-l,2,4- oxadiazo!-5(4H),-one (9c). To a solution of (Z/E)-3,5-dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl)oxy)-N'-hydroxybenzimidamide (9b) (60 mg, 159.73 nmol) in THF (3 mL) was added DSC (53.19 mg, 207.65 umol) and TEA (32.33 rng, 319.46 umol, 44.46 uL).
The mixture was stirred at 60°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was concentrated in vacuum to give 9c (60 mg, crude). The product was used directly for the next step without further purification. MS mass calculated for [M+l]+ (C15H11Q3N4O3) requires m/z 401.0, LCMS found m/z 401.0.
[0285] 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)- l,2,4-oxadiazol-5(4H),-one (Example 9), To a solution of 3-(3,5-dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl)oxy)phenyl)-l,2,4-oxadiazol-5(4H),-one (9c) (60 mg, 149.39 umol) in HO Ac (3 mL) was added NaOAc (49.02 mg, 597.56 umol). The mixture was stirred at 120°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was concentrated in vacuum to give a residue. Hie residue was purified by Prep-HPLC (column: Waters Atlantis T3 150*30*5um; mobile phase: [water (0.225 %FA)-ACN]; B%: 35%-75%, 13mm) to give Example 9. MS mass calculated for j M · 1 G (C15H12CI2N4O4) requires m/z 383.0, LCMS found m/z 383.0; Tl NMR (400MHZ, CD3OD) 5 7.93 (s, 2H), 7.38 (d, J= 0.8 HZ, 1H), 3.17 (spt, J= 6.8 HZ, 1H), 1.29 (d, J = 6.8 HZ, 6H).
Example 10: 3-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)-l,2,4-oxadiazol-5(4H),-one
Figure imgf000089_0001
10c
Example 10
[0286] 3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)benzonitrile (10a). To a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)benzonitrile (9a) (40 mg, 116.75 umol) in HO Ac (4 ml.) was added NaOAc (38.31 mg, 467.01 umol). The mixture was stirred at 120°C for 16 hours. LCMS showed the starting material was consumed completely and the desired MS was found. The mixture was concentrated in vacuum. The solid was dissolved in water and the pH was adjusted to 9 with NaHCCh (4 mL). Then the mixture was partitioned with ethyl acetate 10 mL twice. The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NazSCfl, filtered and concentrated m vacuum to give 10a (34 mg, crude). MS mass calculated for [M+l]÷ (C14H11CI2N3O2) requires m/z 324.0, LCMS found m/z 324.2; ¾ NMR (400MHZ, DMSO) d 12.28 (s, 1H), 8.27 - 8.35 (m, 2H), 7.44 (s, 1H), 3.27 - 3.44 (m, 25H), 2.98 - 3.10 (m, 1H), 1.15 - 1.23 (m, 6H).
[Q287] 3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)benzonitrile (10b). A mixture of 3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)benzonitrile (10a) (34 mg, 104.89 umol) in DMF-DMA (2 mL) was stirred at 110°C for 5 hours under reflux. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was concentrated in vacuum. The residue was partitioned between ethyl acetate (10 mL) and H2O (3 ml.) twice. The combined organic phase wus washed with brine (5 mL*3), dried with anhydrous NazSOr, filtered and concentrated in vacuum to give a residue. The residue wus purified by preparative TLC (petroleum ether: ethyl acetate = 5: 1) to give 10b. MS mass calculated for [M+l]+
(C15H13CJ2N3Q2) requires m/z 338.0, LCMS found m/z 338 0; Tl NMR (400MHZ, CD3OD) 6 8.00 (s, 2H), 7.38 (s, 1H), 3.48 (s, 3H), 3.14 - 3.25 (m, 1H), 1.28 (d, I = 6.85 HZ, 6H).
(Z)-3,5-dichloro-N'-hydroxy-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)benzimidamide (10c). To a solution of 3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo- 1 ,6~dihydropyridazm-3~yi)oxy)benzonitrile (10b) (25 mg, 73.92 umol) in DMF (2 mL) was added NH2OH.HCI (41.10 mg, 591.39 umol) and NaOAc (48.51 mg, 591.39 umol). The mixture was stirred at 80°C for 1 hour. LCMS showed 10b was consumed completely and desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL) and H2O (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na SCri, filtered and concentrated in vacuum to give 10c (25 mg, erode). The product was used directly for the next step without further purification. MS mass calculated for [M+l]+ (C15H16CI2N4O3) requires m/z 371 .1, LCMS found m/z 371 .2.
[0288] 3-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyI)-l,2,4-oxadiazol-5(4H),-one (Example 10), To a solution of (Z)-3,5-dichloro-
N'-hydroxy-4-((5-isopropyl-l -methyl-6-oxo-l,6-dihydropyridazin-3yl)oxy)benzimidaniide (10c) (25 mg, 67.35 umol) in THF (3 mL) was added DSC (22.43 mg, 87.55 umol) and TEA (13.63 mg, 134.69 umol, 18 75 uL). The mixture was stirred at 60°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was concentrated in vacuum to give a residue. The residue was purified by Prep-HPLC (column: Waters Atlantis T3 150*30*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 30%~70%, Drain) to give Example 10. MS mass calculated for [M+l]4· (C16H14CI2N4O0 requires m/z 397.0, LCMS found m/z 397.0; TT NMR (400MHZ, CD3OD) d 7.92 - 7.98 (m, 21 1 ). 7.37 (d, J 0.73 HZ, 1H), 3.48 (s, 3H), 3.12 - 3.26 (m, 1H), 1.28 (d, J = 6.85 HZ, 6H).
Scheme B: 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-
3(2H)-one (Compound l id)
Figure imgf000091_0001
[0289] 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-2-methylaniline (11a). To a mixture of 4-amino-2,6-dichloro-3-methyl-phenol (0.2 g, 1.04 mmol) and 3,6-dichloro-4- isopropyl-pyridazine (la) (198.97mg, 1.04 mmol) in DMSO (5 mL) was added K2CO3 (575.75 mg, 4.17 mmol) and Cul (119.01 mg, 624.86 umoi) at 25°C. Then the mixture was stirred at 90°C for 16 hours. The mixture was added to H2O (25 mL) and extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous NaiSCti, filtered and concentrated in vacuum. The mixture was washed by petroleum ether (5 mL), filtered. The filter cake was concentrated in vacuum to give 11a.
[Q290] 2-(3,5-dichIoro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3-yl)oxy)-2- methylphenyl)isoindoline-l,3-dione (11b). To a mixture of 3,5-dichloro-4-(6-chloro-5- isopropyl-pyndazin-3-yl)oxy-2 -methyl-aniline (11a) (0.4 g, 1.15 mmol) and isobenzofuran-1,3- dione (170.92 mg, 1.15 mmol) in AcOH (10 mL) was added NaOAc (378.63 mg, 4.62 mmol) at 25 °C. Then the mixture was stirred at 120°C for 12 hours. LCMS showed the reaction was completed. The mixture was concentrated to get residue, to the residue -was added to H2O (20 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous NaiSOr, filtered and concentrated in vacuum. The residue was washed by MTBE (5 mL) and filtered. The filter cake w'as concentrated to give 11b. MS mass calculated for [M+l]+ (C22Hi7Cl2N304) required m/z 458.1, LCMS found m/z 458.1 [0291] 2-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoindoline-l,3-dione (11c). A mixture of 2-[3,5-dichloro-4-[(5-isopropyl-6- oxo-lH-pyridazin-3-yl)oxy]-2-methyl-phenyl]isoindoline-l,3-dione (lib) (0.37 g, 807.34 umol) in DMF-DMA (5 mL) was stirred at l 05°C for 4 hours. LCMS showed the reaction was completed. The mixture was added to HbO (20 mL) and extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous NarSOr, filtered and concentrated in vacuum to give 11c. The crude was used next step directly. MS mass calculated for [M+ 1 ] (C22H17G2N3O4) required m/z 472.1 , LCMS found m/z 472.1.
[0292] 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)- one (lid). To a solution of 2-[3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-pyridazin-3-yl)oxy- 2-methyl-phenyl]isoindoline-l,3-dione (11c) (440 mg, 931.57 umol) in MeOH (1 mL) were added butan-l-amine (2 M, 1.40 ml.) at. 70°C .Tire mixture was stirred at 70°C for 1 hour. Tire mixture w¾s concentrated in vacuum. The residue was purified by prep-TLC (S1O2, petroleum ether /ethyl acetate:=: 1 : 1) to give lid. MS mass calculated for [MtTj^CirHnChNiQr) required m/z 342. L LCMS found m/z 342.1. !H NMR (400 MHz, CD3OD) d 7.22 (s, 1H), 6.77 (s, 1H), 3.50 (s, 3H), 3.20 - 3.14 (nr, 1H), 2 20 (s, 3H), 1.25 (d, I = 6.8 Hz, 6H).
Example 11 : N-(3,5-diehloro-4-((S~isopropyI~l-methyl-6~oxo-l ,6-dihydropyridazin-3- yl)oxy)-2-methylphenyI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carboxamide
Figure imgf000092_0001
[0293] N-(3,5-dichloro-4-((5-isopropyI-l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-2-
Figure imgf000092_0002
solution of 6-(4-amino-2,6-dichloro-3-methy]phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)- one (lid) (20.85 mg, 60.94 umol ) in THF (3 mL) was added TEA (18.50 mg, 182.82 nmol) and 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carbonyl chloride (4e) (13.57 mg, 91.41 umol). The mixture was stirred at 25°C for 0.5 hours. TLC showed l id was consumed. The reaction mixture was quenched by addition MeOH (1 mL) at 25 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Xtimate C18 l50*25mm*5um; mobile phase: [water (lOmM NH4HC03)-ACN]; B%: 20%-50%, I Omin) to give Example 11. MS mass calculated for [M+l]+( CisHnCbNsOs) required m/z 454.1 , LCMS found m/z 454.1; ¾ NMR (400 MHz, CD3OD) d 7.77 (s, 1H), 7.31 (d, I = 0.7 Hz, !H), 3 49 (s, 3H), 3.23 - 3.1 1 (m, i l l). 2.38 (s, 31 1). 1.27 (d, I = 6.8 Hz, 6H).
Example 12: 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)-2-methylphenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one
Figure imgf000093_0001
[Q294] 2-|3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl- anilino] acetonitrile (12a). To a solution of 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4- isopropyl-2-methylpyridazin-3(2H)-one (lid) (50 mg, 146.10 umol) in ACN (1 mL) was added 2-bromoacetonitrile (87.62 mg, 730.52 umol, 48.68 uL), Nal (43.80 mg, 292.21 urnol) and K2CO3 (40.39 mg, 292.21 umol). The mixture was stirred at 100°C for 16 hours. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (5 mL*3). The combined filtrates were concentrated to give a residue. The residue was purified by Prep-TLC (SiCb, petroleum ether : ethyl acetate:=: 1 : 1) to give (12a). 1HNMR (400MHz, CDCb) S 7.04 (s, 1H), 6 71 (s, 1H), 4 20 (d, I = 6.6 Hz, 2/H), 4.13 (q, J = 7.2 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.53 (s, 3H), 3.31 - 3.16 (m, 1H), 2.27 (s, 3H), 1 59 (br s, 4H), 1 .38 - 1.15 (m, 8H).
[0295] tert-butyl N-(cyanomethyl)-N-[3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo- pyridazin~3~y!)oxy~2-methyi-phenyi]carbamate (12b). To a solution of 2-[3,5-dichloro-4-(5- isopropyi-l-methyl-0-oxo-pyridazin-3-yl)oxy-2-methyl-anilino]aeetonitrile (12a) (55 mg, 144.26 umol) in THF (1 mL) was added B0C2G (94.45 mg, 432.78 umol, 99.42 uL) and DMAP (17.62 mg, 144.26 nmol). The mixture was stirred at 40°C for 1 hour. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was partitioned between ethyl acetate (10 mL) and H2O (3 mL) twice. The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NarSOr, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate^ 3: 1 ) to give 12b. MS mass calculated for [M+l]+ (C22H26Q2N4O4) required m/z 481.1, LCMS found m/z 481.1: lH NMR (400MHz, CDCI3) S 7.04 (d, J = 1.0 Hz, 1H), 4.57 - 4.27 (m, 2H), 3.48 (br s, 31 1). 3.28 - 3.16 (m, 11 1). 2 29 (s, 3H), 1 66 - 1.47 (m, 10H), 1 38 (hr s, 6H). [Q296] tert-butyl N-[(2Z)-2-amino-2-hydroxyimino-ethyl]-N-[3,5-dichloro-4-(5-isopropyl- l-methyl-6-oxo-pyridazin-3-yl)oxy-2-methy 1-phenyl] carbamate (12c). To a solution of tert- butyl N-(cyanomethyl)-N-[3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-pyridazin-3-yl)oxy-2- methyl -phenyljcarbamate (12b) (40 mg, 83.10 umol) in DMF (1 mL) was added NH2OH.HCI (46 19 mg, 664.77 umol) and NaOAc (54.53 mg, 664.77 umol). The mixture was stirred at 80°C for 1 hour. The residue was partitioned between ethyl acetate (10 mL) and H2O (3 mL) twice. The combined organic phase was washed with brine (5 mL* 3), dried with anhydrous NaiSOy filtered and concentrated in vacuum. The residue was purified by Prep-TLC (S1O2, petroleum ether : ethyl acetate^ 1: 1) to give 12c. MS mass calculated for [M+l]+
(C22H29CI2N5Q5) required m/z 514.2, LCMS found m/z 514.2; ¾ NMR (40GMHz, CDCb) <5 7.16 (s, 1H), 7.05 (d, J = 1.0 Hz, 1H), 5.27 (br s, 2H), 3.50 (s, 3H), 3 33 - 3.17 (m, 1H), 2.25 (s, 4H), 1.39 (s, 8H), 1.28 - 1.26 (m, 71 1 ).
[0297] tert-butyl N-[3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-pyridazin-3-yl)oxy-2- methyl-phenyl]-N-[(5-oxo-4H-l,2,4-oxadiazol-3-yl)methyl]carbamate (12d). To a solution of tert-butyl N-[(2Z)-2-amino-2-hydroxyimino-ethyl]-N-[3,5-dich]oro-4-(5-isopropyl-l -methyl-6- oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]carbamate (12c) (40 mg, 77.76 umol) in THF (1 mL) was added DSC (25.90 mg, 101.09 umol) and TEA (15.74 mg, 155.52 umol, 21.65 uL). Hie mixture was stirred at 60°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was partitioned between ethyl acetate (10 mL) and H2.O (3 mL). Twice. The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NacSOy filtered and concentrated in vacuum to give a residue.
The residue was purified by prep-TLC (SiCh, DCM: MeOH= 5: 1) to give 12d. MS mass calculated for [M+l]+ (C22H29CI2N5O5) required m/z 540.1, LCMS found m/z 540.1.
[0298] 3-| [3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl- anilino]methyl]-4H-l,2,4-oxadiazol-5-one (Example 12). To a solution of tert-butyl N-[3,5- dichloro-4-( 5 -isopropyl- 1 -methyl-6-oxo-pyri dazin-3 -yl)oxy-2 -methyl -phenyl ] -N- [(5 -oxo-4H- 1, 2, 4-oxadiazol-3-yl)methyl] carbamate (12d) (30 mg, 55 51 umoi) in EtOAc (1 mL) were added HCl/EtOAc (2 M, 27.76 uL) at 25°C .The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (HCI condition) to give Example! 2 MS mass calculated for [M+l]+
(C22FI29Q2N5O5) required rn/z 440.1 , LCMS found m/z 440 2. Ή NMR (400MHz, CD3OD) <5 7.24 (s, 1H), 6.72 (s, 1H), 4.37 (s, 2H), 3.48 (s, 3H), 3.23 - 3.11 (m, 1H), 2.29 (s, 3H), 1.26 (d, J = 6.8 Hz, 6H).
Scheme C: 6-(4-ammo-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (Compound
Figure imgf000095_0001
[0299] ethyl 2-cyano-2-(2,6-dichloro-4-nitrophenyl)acetate (13a). To a suspension of NaH (1.41 g, 35.33 mmol, 60% purity) in DMSQ (40 mL) was added ethyl 2-cyanoacetate (4.00 g, 35.33 mmol) drop wise at 0°C and stirred at !5°C for 30 minutes, then i ,2,3~trichloro-5- nitrobenzene (4 g, 17.66 mmol) was added, the resulting mixture was stirred at 15°C for 16 hours. Then the mixture was quenched with water ( 100 mL) and adjusted to pH=l with 1 M HCI. And the white precipitate was collected by filtration and dried over in vacuum. The solid was washed with petroleum ether (40 mL) and dried in vacuum to give 13a. Ή NMR (400 MHz, CDC13) d 8.32 (s, 2H), 5.72 (s, 1H), 4.38 (q, J -- 7.1 Hz, 2H), 1.37 (t, J -- 7.2 Hz, 3H).
[0300] 2-(2,6-dichloro-4-nitrophenyl)acetonitrile (13b) A mixture of ethyl 2-cyano-2~(2,6~ dichloro-4-nitrophenyl)acetate (13a) (1 .7 g, 5 61 mmol) and Li Cl (285.33 mg, 6.73 mmol) in DMSO (6 mL), H2O (2.5 mL) was heated to 165°C for 1 hour. After cooling, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL*2), the organic phases were washed whh brine, dried over Na2S04, filtered and concentrated to give 13b. !H NMR (400 MHz, CDCb) 6 8.21 (s, 2H), 4.03 (s, 2H).
[0301] 2-(4-amino-2,0-dicMorophenyl)acetomirile (13c). A mixture of 2-(2,6-dichloro-4- nitrophenyl)acetonitrile (13b) (1 g, 4.33 mmol) and Fe (1.21 g, 21.64 mmol) in HOAc (10 mL) was heated to 15°C for 1 hour. TLC showed new point, the mixture was filtered, the filtrate was added water ( 100 mL) and extracted with ethyl acetate (50 mL), the organic phase was neutralized with sat. NaHCCb (20 mL*2), washed with brine (20 mL), dried over Na SOr, filtered and concentrated to give 13c. ¾ NMR (400 MHz, CDCb) d 6.67 (s, 2H), 3.88 (s, 4H).
[0302] 2-(4-amino-2,6-dich!orophenyl)-2-(6-chloro-S~isopropy!pyridaz!n-3-yl)acetonitriIe (13d). To a solution of 2-(4-amino-2,6-dichlorophenyl)acetonitrile (13c) (0.43 g, 2.14 mmol) and 3,6-dichloro-4-isopropylpyridazine (la) (408.62 mg, 2.14 mmol) in THF (5 mL) was added t-BuOK (1 M, 4.28 mL) drop w ise at 60°C, the resulting mixture was heated to 60°C for 40 minutes. After cooling, the mixture was diluted with ethyl acetate (20 ml.) and washed with brine (20 mL). The organic layer was separated, dried with NaiSOy filtered and concentrated, the residue was purified by silica gel chromatography (petroleum ether : ethyl acetate= 5: 1) to give 13d. MS mass calculated for [M+l]+( C15H13CI3N4) required m/z 355.0, LCMS found m/z .355.1; Ή NMR (400 MHz, CDCb) d 7.60 (s, 1H), 6.69 (s, 2H), 6.33 (s, 1H), 3.99 (br s, 2H), 3.33 (td, I = 6.8, 13.6 Hz, 1H), 1.32 (dd, J - 4.0, 6.8 Hz, 6H).
[0303] 6-(4-ammo~2,6~dich!orobenzyI)-4-isopropylpyridazm-3(2H)~one (13e). A solution of 2~(4-amino-2,6-dich!orophenyl)-2~(0-chloro-5~isopropyipyridazin~3-y!)acetonitri!e (13d) (0.15 g, 421.76 umol) in HO Ac (0.6 mL), H2O (0.6 mL) and conc.HCl (2.4 mL) was heated to 120°C for 32 hours. LCMS showed desired MS. After cooling, the mixture was adjusted to pH~7 with 4M NaOH at 0°C, the solid was filtered and dried to give 13e as off white solid, the solid was used for the next step directly. MS mass calculated for [M+l]+ (C14H1SCI2N3O) required m/z 311.0, LCMS found m/z .311.1.
Example 13: N-(3,5-dichloro-4-((5-isopropyI-6-oxo-l,6-dihydropyridazin-3- yI)methyl)phenyS)-5-oxo-4,5-dihydro-l,2,4-oxadiazoIe-3-carboxamide
Figure imgf000096_0001
[0304] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3-yl)oxy)phenyl)-5- oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 13). To a solution of 6-(4- amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (13e) (20 mg, 64.06 umol) in THF (3 mL) was added TEA (19.45 mg, 192 19 umol) and 5-oxo-4, 5-dihydro-1 , 2, 4-oxadiazole-3- carbonyl chloride (4e) (14.27 mg, 96.09 urnol, 1.5 eq). The mixture was stirred at 25°C for 0.5 hours. TLC showed 13e was consumed completely. Hie reaction mixture was quenched by addition MeOH (1 mL) at 25 °C, and then concentrated under reduced pressure to give a residue. The residue was checked by HPLC and purified by Prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 5%-35%, 10mm) to give Example 13. MS mass calculated for [M+lj 'TCnHisCkN Qr) requires mJz 424.0, LCMS found m/z 424.0. Tl NMR (400 MHz, CD3OD) d 7.87 (s, 2H), 7.23 (s, 1H), 4.30 (s, 2H), 3.16 - 3.04 (m, 1 1 1 ). 1.20 id. ./ 7.1 Hz, 61 1).
Example 14: N-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yI)methyl)phenyl)-5-oxo-4, 5- dihydro-1, 2, 4-oxadiazoIe-3-carboxamide
Figure imgf000097_0001
[0305] 6-(4-ammo~2,6~dich!orobenzyl)-4-isopropylpyridazm-3(2H)~one (14a). To a solution of 2-(4-amino-2,6-dichloropheny])-2-(6-chloro-5-isopropylpyridazin-3-yl) acetonitrile (13d) (1.5 g, 4.22 mmol) in con. HCI (16 mL) and HOAc (2 mL) was added H2O (2 mL). Hie mixture was stirred at 120°C for 72 hours. LCMS showed the desired mass. The mixture was adjusted to pH= 7 by addition of 6 M aqueous sodium hydroxide solution. The suspension was stirred for 15 minutes. The resulting solid was filtered and washed with H2O and petroleum ether. Hie residue was purified by column chromatography (petroleum ether: ethyl acetate= 5 : 1 to 1 : 1) to give 14a. !HNMR (400 MHz, DMSOd6) 5 12.59 (s, 1H), 7.12 - 7.10 (m, 1H), 6.62 (s, 2H), 5.60 (s, 2H), 3.99 (s,
Figure imgf000097_0002
2.96 (td, J = 6.9, 13.5 Hz, i l l). 1.11 (d, .1 = 6.8 Hz, 6H) [0306] 2-(3,5-dich!oro-4-((S-isopropyS-6-oxO l,6-dihydropyridazin-3- yI)methyl)phenyS)isoindoSine-l,3-dione (14b). A solution of 6-(4-ammo-2,6-dichlorohenzyl)- 4-isopropylpyridazin-3(2H)-one (14a) (450 mg, 1.44 mmol) in AcOH (5 mL) was added isobenzofuran~l ,3~dione (213.50 mg, 1.44 mmol). The mixture was stirred at 130°C for 4 hours. LCMS showed desired mass. The reaction mixture was concentrated under reduced pressure to remove AcOH. Tins mixture was extracted with water (50 mL) and Ethyl acetate (50 mL), and then washed with NaHCCb (20 mL*3), dried over NaiSO-», filtered and concentrated under reduced pressure to give 14b. The product was used in next step without further purification.
MS mass calculated for [M+l]+( C22H17CI2N3O3) required m/z 442.1 , LCMS found m/z 442 1.
[0307] 2~(3,5~dichloro-4~((5-isopropyS-l-methy!-6-oxo~l,6-dihydropyridazin-3- yI)methyS)phenyi)isoindoiine-l,3-dione (14c). A mixture of 2-(3,5-dichloro-4-((5-isopropyl-6- oxo-1 , 6~dihydropyridazm-3~yl)methy])phenyl)isoindoline~l ,3~dione (14b) (600 mg, 1.36 mmol) and DMF-DMA (5 mL) was heated to l05°C for 3 hours. LCMS showed desired mass. The reaction mixture was and concentrated under reduced pressure to give 14c. The product was used in next step without further purification. MS mass calculated for [M+!]+ (C23H19CI2N3Q3) required m/z 456.1 , LCMS found m/z 456.1.
[0308] 0-(4~amino~2,6~dkh!orobenzyI)-4~isepropyl-2-methy!pyridiizin-3(2H)-one (14d). A solution of 2 -(3 , 5 -dichloro-4-((5 -isopropyl- 1 -me thyi-6-oxo- 1 ,6-dihydropyridazin-3 - yi)methyl)pheny!)isoindolme-l,3-dione (14c) (600 mg, 1.31 mmol) in N-buty!amine (981 . i l mg, 6.57 mmol) and MeOH (3 mL) was heated to 70°C for 3 hours. TLC showed reaction was completely. LCMS showed desired mass. The reaction mixture concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether : ethyl acetate= 3: 1 to 2: 1 ) to give I4d. MS mass calculated for [M+l ]+ (C18H17Q2N5O4) required m/z 326.1 , LCMS found m/z 326.0. Ή NMR (400 MHz, CD3OD) d 7.08 - 7.04 (m, 1H), 6.72 - 6.69 (m, 2H), 4.13 (s, 2H), 3.70 (s, 3H), 3.14 - 3.06 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H).
[0309] N-(3,S-dichloro-4-((5-isopropyI-l-methyT-6-oxo-l,6-dihydropyridazin-3- yT)methyS)phenyl)~5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 14). A solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (14d) (19.43 mg, 59.78 umol) iu DCM (2 mL) was added TEA (18.15 mg, 179.33 umol, 3eq) and 5- oxo-4,5-dihydro-l,2,4-oxadiazole-3-carbonyl chloride (4e) (8.88 mg, 59.78 umol). The mixture was degassed and purged with N2 for 3 times stirred at 25 °C for 0.5 hours. Hie reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (NH4CO3) to give Example 14. MS mass calculated for [M+l]+(
C18H17C12N504) required m/z 438.1 , LCMS found m/z 438.0; IH NMR (400 MHz, CD30D) d 7.89 (s, 2H), 7 18 (s, 1H), 4 30 (s, 2H), 3.69 - 3 63 (m, 3H), 3.13 (td, J = 7.0, 13.8 Hz, 1H), 1.19 (d, I = 6.8 Hz, 6H).
Example 15: 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3- yl)methyl)phenyl)amino)methyl)-l,2,4-oxadiazoI-5(4H)-one
Figure imgf000099_0001
[0310] 6-{4-amino-2,6-dichlorobenzyI)-4-isopropyI-2-{4-methoxybenzyl)pyridazin 3(2H}- one (15a), To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (13e) (200 mg, 640.63 umol) in DMF (5 mL) was added PMB-C1 (120 39 mg, 768.75 umol), K2CO3 (106.25 mg, 768.75 umol). The mixture was stirred at 20°C for 16 hours. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH (5 mL*3). The combined filtrates were concentrated to dryness to give a residue. The residue was purified by prep-TLC to give 15a. Ή NMR (400 MHz, DMSO-de) S ppm 7.17 (d, J ::: 8.6 Hz, 2H), 7.04 (s, 1H), 6.85 - 6.80 (m, 2H), 6.65 (s, 2H), 5.63 (s, 2H), 5.02 (s, 21 1). 4.01 (s, 2H), 3.71 (s, 3H), 2 97 (td, J = 6.8, 13.5 Hz, 1H), 1.07 (d, I = 7 1 Hz, 6H)
[0311] 2-((3,5-dichloro-4-((5-isopropyl-l-(4-methoxybenzyI)-6-oxo-l,6-dihydropyridazin- 3-yl)methyl)phenyl)amino)acetonitrile (15b). To a solution of 6-(4-amino-2,6- dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazin-3(2H)-one (15a) (150 mg, 346.95 umol) and 2-bromoacetonitrile (416.16 mg, 3.47 mmol) in DMF (10 mL) was added K2CO3 (57.54 mg, 416.34 umol) and KI (28.80 mg, 173.47 umol). The mixture was stirred at 100°C for 6 hours. The reaction mixture was quenched by addition water 5 mL, and then extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous NazSOi, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Si02, petroleum ether : ethyl acetate- 1 : 1, according TLC) to give 15b. ! ! NMR (400 MHz, DMSO-de) d 7.15 (d, J = 8.6 Hz, 21 1). 7.12 (s, 1H), 6.87 (s, 2H), 6 83 (d, J = 8.8 Hz, 2H), 6.76 (t, J = 6.7 Hz, 1H), 5 00 (s, 2H), 4.37 (d, J = 6.6 Hz, 2H),
4.08 (s, 2H), 3.71 (s, 3H), 2.99 (td, J = 6.7, 13.7 Hz, 1H), 1.08 (d, I = 6.8 Hz, 6H).
[0312] tert-butyl (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-l-(4-methoxybenzyI)-6-oxo-
1.6-dihydropyridazin-3-yl)methyl)phenyl)carbamate (ISc). To a solution of 2-((3,5-dichloro- 4-((5-isopropyl-l -(4-methoxybenzyl)-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)amino)acetonitrile (15 b) (133 mg, 282 15 umol) in THF (3 mL) was added DMAP (34.47 mg, 282, 15 umol) and BocrO (184.74 mg, 846.45 umol). The mixture was stirred at 20°C for 1 hour. The reaction was clean according to TLC. LCMS showed one main peak with desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. Tie residue was purified by prep-TLC (SiCh, petroleum ether : ethyl acetate = 1 : 1, according TLC) to give 15c. MS mass calculated for [M+l]+ (C29H32CI2N4Q4) required m/z 571.2, LCMS found m/z 471.1/571.1; l !W!R (400 MHz, CD3CI) d 7.35 - 7.33 (m, 21 1).. 7.31 (s, 1H), 6.91 (s, IH), 6.82 (d, I = 8.8 Hz, 2H), 5.13 (s, 2H), 4.49 (s, 2H), 4.24 (s, 2H), 3 78 (s, 3H), 3.16 (quin, J = 6.9 Hz, 11 1). 1.51 (s, 9H), 1.15 (d, J = 6.6 Hz, 61 1).
[0313] (Z)-tert-butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-l-(4- methoxybenzy!)~6~oxo-l,6-dihydropyridazin~3~y!)niethy!)phenyl)carbamate (15d). To a solution of tert-butyl (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-l-(4-methoxybenzyl)-6-oxo-
1.6-dihydropyndazin-3-yi)methyl)phenyl)carbamate (15c) (100 mg, 174.98 umol) in DMF (3 mL) was added NH2OH.HCI (97.27 mg, 1.40 m ol) and NaOAc (114.83 mg, 1.40 mmol). The mixture was stirred at 80°C for 6 hours. LCMS showed one main peak with desired MS Tie suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (5 mL*3). The combined filtrates were washed with brine 10 mL, dried over anhydrous NazSQi, filtered and concentrated under reduced pressure to give 15d was used into the next step without further purification as an off-white gum. MS mass calculated for [M+l ]+ (C14H15CI2N3O2) required m/z 604.2, LCMS found m/z 504.2/604.2; >H NMR (400 MHz, DMSO-de) d 9.15 (s,
1 1 1). 7.51 (s, 2H), 7.18 (s, IH), 7.11 (d . ,/ 8.6 Hz. 21 1). 6.82 (d, ./= 8 6 Hz, 2H), 5.40 (s, 2H), 4.96 (s, 2H), 4.21 (s, 2H), 4.19 (s, 2H), 3.71 (s, 3H), 2.99 (td, J= 6.8, 13.5 Hz, IH), 1.38 (s, 9H), 1.09 (d, J = 6.8 Hz, 61 1).
[0314] tert-butyl (3,5-dichloro-4-((5-isopropyl-l-(4-methoxybenzyl)-6-oxo-l,6- dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)methyl)carbamate (15e). To a solution of (Z)-tert-butyl (2-amino-2- (hydroxyimino)ethy3)(3,5-dichloro-4-((3-isopropyl-l~(4-methoxybenzyl)~6-oxo~l,6~ dihydropyridazin-3-yl)methyl)phenyl)carbamate (15d) (40.00 mg, 66.17 umol) in THF (3 mL) was added TEA (13.39 mg, 132.34 umol) and DSC (22.04 mg, 86.02 umol) at 0°C.The mixture was stirred at 65°C for 16 hours. LCMS showed one main peak w ith desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (dichloromethane: methanol ::: 10: 1) to give 15e. MS mass calculated for [M+l]÷( C30H33CI2N5O6) required m/z 630.1, LCMS found m/z 630.1.
[0315] tert-butyl (3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)((5-oxo-4,5-dihydro-l ,2,4-oxadiazoI-3-yl)methyl)carbamate (15f). To a solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-l-(4-methoxybenzyl)-6-oxo-l,6- dihydropyridazin~3-yl)methyl)phenyl)((5~oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)methyl)carbamate (15e) (17 mg, 21.57 umol) in ACN (2 mL) and ITO (0.5 mL) was added CAN (47.30 mg, 86.28 umol). The mixture was stirred at 20°C for 4 hours. TLC showed 15e was remained -10% and one new spot was formed. The reaction mixture was concentrated under reduced pressure to remove ACN. The residue was diluted with brine 5 mL and extracted with EtOAe 30 mL (10 mL *3). The combined organic layers were washed with brine 10 mL, dried over anhydrous NarSOr, filtered and concentrated under reduced pressure to give 15f. MS mass calculated for [M+ 1 ]+ (C22H25CI2N5O5) required m/z 510.1, LCMS found m/z 510.1.
Figure imgf000101_0001
yl)methyl)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one (Example 15). A solution of tert-butyl (3,5-dichioro-4-((5-isopiOpyl-6-oxo-l,6~dihydropyridazin-3-yl)methyl)phenyi)((5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (15f) (33 mg, 64 66 umoi) in EtOAe (2 mL) and HCl/EtOAc (2 M, 161 65 uL) was stirred at 20°C for 1 hour. TLC indicated starting material was consumed completely and one new spot was formed LCMS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove EtOAe The residue was purified by prep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.04%HC1)-ACN]; B%: 25%-50%, 12min) to give Example 15. MS mass calculated for j \ I · ί G ί(':-1 1:-P L -.ίK} required m/z 410.0, LCMS found m/z 410.0. ¾ NMR (400 MHz, CDsQD) d 7.12 (s, i l l). 6.76 (s, 2H), 4.28 (s, 2H), 4.17 (s, 2H), 3.08 (td, ./= 6 9, 13 6 Hz, 1 1 1}. 1.17 (d, = 6.8 Hz, 6H).
Example 16: 3-(((3,5-dkhloro-4-((5-isoprGpy!-l-meihyt-6-oxG-l,6-dihydropyridazm-3- yl)methyS)phenyi)am!no)methyi)~l ,2,4-oxadiazol-5(4H)-one
Figure imgf000102_0001
yl)met y!)phenyl)amino}acetonitri!e (16a). To a solution of 6-(4-amino-2,6-dichlorobenzyl)- 4 isopropyl-2-methylpyndazin-3(2H)-one (14d) (150 mg, 459.81 umol) and 2-bromoacetonitrile (551.53 mg, 4.60 mmol) in DMF (5 mL) was added KI (38.16 mg, 229.91 umol) and K2CO3 (76.26 mg, 551.77 umol). The mixture was stirred at 100°C for 8 hours. LCMS showed desired mass. After cooling, the reaction mixture was partitioned between ethyl acetate (20 mL) and H2O (20 mL). The organic phase was separated, washed with brine ( 10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether : ethyl acetate = 2: 1) to give 16a. *HNMR (400 MHz, DMSO-ds) <5 7.10 (s, 1H), 6.85 (s, 2H), 6.75 (t, J = 6.7 Hz, 1H), 4.35 (d, J = 6.6 Hz, 21 1). 4.07 (s, 2H), 3.53 (s, 3H), 3.01 (td, J = 7.0, 13.7 Hz, 1H), 1.10 (d, J = 6.8 Hz, 6H).
[0318] tert-bufy! (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-l -methyI-6-oxo-l,6- dihydropyridazin-3-yl)methyl)phenyl)carbamate (16b). A mixture of 2-((3,5-dichloro-4-((5- isopropyl- 1 -methyl-6-oxo- 1 ,6-dihydropyridazin~3-yl)metliyl)phenyl)amino)acetonitnle (16a)
(20 mg, 54.76 umol), DMAP (6.69 mg, 54.76 umol) and B0C2O (119.50 mg, 547.56 umol) in TOP (2 mL) was stirred at 20°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Hie residue was purified by prep-TLC (petroleum ether : ethyl acetate = 2: 1) to give 16b. !H NMR (400 MHz, CD3OD) d 7.45 (s, 2H), 7 22 - 7.19 (m, 1H), 4.67 - 4.64 (m, 2H), 4.35 - 4.32 (m, 2H), 3.66 - 3.62 (m, 3H), 3 17 - 3.09 (m, 1H), 1.51 - 1.47 (m, 9H), 1.19 (d../ 7.0 Hz, 6H).
[0319] (Z)-tert-butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-l- methyl-6-oxo-l,6-dihydropyridazin-3-yl)methyl)phenyl)carbamate (16c). To a solution of tert-butyl (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)carbamate (16b) (50 mg, 107.44 umol) in DMF (2 mL) was added
NH2.GH.HCl (37.33 mg, 537.20 umol) and NaOAc (44.07 mg, 537.20 umol). The mixture was stirred at 80°C for 1 hour. LCMS showed desired mass. The reaction mixture was partitioned between ethyl acetate (20 mL) and H2O (20 mL). Tire organic phase was separated, washed with brine (20 mL), dried over Na2.Si)4, filtered and concentrated under reduced pressure to give 16c without further purification. MS mass calculated for | M 1 1 (C22H29CI2N5O4) required m z 498.2, LCMS found m/z 498.2
[032Q] tert-butyl (3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (16d). To a solution of (Z)-tert-butyl (2-aniino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-l- methyl-6-oxo-l,6-dihydropyridazin-3-yl)nrethyl)phenyl)carbamate (16c) (26 mg, 52.17 umol) in THF (2 mL) was added DSC (17.37 mg, 67.82 umol) and TEA (10.56 mg, 104.33 umol). The mixture was stirred at 60°C for 16 hours. After cooling to room temperature, tire reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane: methanol = 10: 1) to give 16d. MS mass calculated for [M+l]÷
( C23H27C32N5Q5) required m/z 524.1, LCMS found m/z 524.1.
[0321] 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- y!)methyl)phenyS)amino)inethyS)-l,2,4-oxadiazoI-5(4H)-one (Example 16). To a solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)((5-oxo-4,5-diiiydro-l,2,4-oxadiazol-3-yi)methyl)carbamate (16d) (24 mg, 45 77 umol) in EtOAc (1 mL) was added EtOAc/HCl (4 M, 11.44 uL). The mixture was stirred at 20°C for 2 hours. LCMS showed desired mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA) to give Example 16. MS mass calculated for [M+lj '^CisHmChNsOi required m/z 424.1, LCMS found m/z 424.1. Ή NMR (400 MHz, CD3OD) d 7.10 - 7.06 (m, 1H), 6.76 (s, 2H), 4.27 (s, 21 0. 4.16 (s, 2H), 3.70 - 3.67 (m, 3H), 3.14 - 3.06 (m, 1 H), 1.15 (d, ./ 6.8 Hz, 6H).
Example 17: N-(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000104_0001
[Q322] {4-ammo-2,6 dichIoropheoyl)(6-chloro-5-isopropyIpyridazin 3-yS)methaoone (17a). To a solution of 2-(4~ammo~2,6~dichloro~phenyl)-2-(6~ehloro-5~isopropyi~pyridazm-3~ yljacetonitrile (13d) (0.9 g, 2 53 mmol) in CLLCN (20 mL) was added t-BuOK (1 M, 2.40 mL) at 20°C. And the mixture was stirred at 20°C for 0 5 hours. Then the mixture was cooled to 0°C and H2O2 (573.85 mg, 5.06 mmol, 486.31 uL, 30% purity) was added in the mixture by dropwise. Then the mixture was stirred at 0°C for 0.5 hours, and stirred at 20°C for another 2 hours. Then saturated NaiSO solution (5 mL) was added in the mixture, and the mixture was stirred at 20°C for 1 hour. Then the mixture was concentrated in vacuum to remove CHbCN. The residue was extracted with EtOAc (10 mL*2). The combined organic layer was washed with brine (5 mL), dried over NaiSOi, filtered and concentrated in vacuum. The residue was purified by column silicagel chromatography (petroleum ether : ethyl acetate:=30: 1 to 5: 1) to give 17a. MS mass calculated for [M+l]+( C14H12Q3N3Q) required m/z 344.0, LCMS found m/å 344.0/346.0; TiNMR (400 MHz, DMSO-de) d 8.24 (s, 1 H) 6.67 (s, 2 H) 6 21 (s, 2 H) 3.18 - 3.31 (m, 1 H) 2.50 (br s, 5 H) 1.27 - 1.39 (m, 6 H).
[0323] 2-(3,5-dichloro-4-(5-isopropyl-6-oxo-l,6-dihydropyridazine-3- carbonyi)phenyI)isomdoIine-l,3-dione (17b). To a solution of (4-amino-2.,6~
dichlorophenyl)(6-chloro-5~isopropylpyridazin~3-y!)methanone (17a) (260 mg, 797.1 1 umol) in HOAc (10 mL) was added NaOAc (326.94 mg, 3.99 mmol) and isobenzofuran-l ,3-dione (129.87 mg, 876.82 umol). The mixture was stirred at 120°C for 1 hour. LCMS showed the desired mass. The mixture was concentrated in vacuum, the residue was diluted in H2O (50 mL*2) and NaHCOi (50 mL*2). Then the mixture was extracted with ethyl acetate (30 mL 2). The combined organic layer was concentrated in vacuum. The residue was purified by prep- TLC to give 17b, MS mass calculated for [M+l]+( C22H15CI2N3Q4) required m/z 456.0, LCMS found m/z 456.0.
[0324] 2-(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazine-3- carbonyl)phenyl)isoindoline-l,3-dione (17c). To a solution of 2-(3,5-dichloro-4-(5-isopropyl-
6-oxo-l,6-dihydropyridazine-3-carbonyl)pheny])isoindoline-l,3-dione (17b) (250 mg, 547.91 umol) in DMF-DMA (30 mL), the mixture was stirred at 110°C for 3.5 hours. LCMS showed desired mass. The reaction mixture was partitioned between H2O 30 mL*2 and EtOAc 30 mL*2. Tire organic phase was concentrated under reduced pressure to give 17c. The erode product was used into the next step without further purification. MS mass calculated for [M+l]+ (C23H17Q2N3O4) required m/z 470.1, LCMS found m/z 470.1.
[0325] 6-(4-amino~2,6~dich!orobenzoyl)-4 isopropyl-2-methylpyridazin-3(2H)-one (17d). To a solution of 2-(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazine-3- carbonyl)phenyl)isoindoline-l,3-dione (17c) (200 mg, 425.26 umol) in MeOH (2 mL) was added N-butylamine (190.39 mg, 1.28 mmol, 204.72 uL). The mixture was stirred at 70°C for 0.5 hours. LCMS showed desired mass. The mixture was concentrated under vacuum. The residue was purified by prep-TLC to give 17d. MS mass calculated for [M+ 1]+ (C15H15CI2N3O2) required m/z 340.1, LCMS found /z 340.1; ¾NMR (400 MHz, CD3QD) d 7.85 (d, J = 0.9 Hz, 1H), 6.64 (s, 2H), 3.76 - 3.72 (m, 4H), 3.22 - 3.14 (m, 1 1 1}. 1.29 - 1.26 (m, 7H).
[0326] N-(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 17). To a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (17d) (20 mg, 58.79 umol) in THF (5 mL) was added TEA (17.85 mg, 176.36 umol) and 5-oxo~4,5- dihydro-l,2,4-oxadiazole-3~carbonyi chloride (4e) ( 13.10 mg, 88.18 umol). The mixture was stirred at 25°C for 0.5 hours. LCMS showed desired MS wras detected. The reaction mixture was quenched by addition MeOH 1 mL at 25 °C, and then concentrated under reduced pressure to give a residue. The residue was checked by HPLC and purified by Prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (lOmM NH4HC03)-ACN]; B%: 20%-40%, 10mm) to give Example 17. MS mass calculated for [M+l]+( C18H15C12N505) required m/z 452.0, LCMS found m/z 452.0; ¾ NMR (400 MHz, CD30D) d 7.94 (br s, 2H), 7.93 (br d, J = 2.9 Hz, 1H), 3 73 (s, 3H), 3.26 - 3 1 1 (m, 1H), 1.30 (br d, I = 6 7 Hz, 6H). Example 18: 3-(((3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazine-3·
Figure imgf000106_0001
[0327] 2-((3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazine-3- carbonyl)phenyl)amino)acetonitrile (18a). To a solution of 6-(4-amino-2,6-dichlorobenzoyl)-
4-isopropyl-2-meth\Tpyridazm-3(2H)-one (72 mg, 211.64 umol) (17d) in MeCN (2 mL) was added 2-bromoacetonitrile (126.93 mg, 1.06 mmol, 70.52 uL), Nal (63.45 mg, 423.28 umol) and K2CO3 (58.50 mg, 423.28 umol). The mixture was stirred at I 00°C for 13 hours. The reaction mixture was extracted with ethyl acetate (20 mL*2) and H2O (20 mL*2). The combined organic layers were washed with brine (20 mL), dried over NazSOr filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether : ethyl acetate= 1 : 1) to give 18a MS mass calculated for [M+1] (C17H16CI2N4O2) required m/z
379.1, LCMS found m/z 379.2;‘H NMR (400 MHz, CDCh) d 7.84 (d, J = 0.7 Hz, i l l }. 6.68 (s, 2H), 4.16 (d, J = 6.8 Hz, 2H), 3.77 (s, 3H), 3.27 - 3.19 (m, 1H), 1.28 (d, J = 6.8 Hz, 61 1).
[0328] tert-fouty! (cyanomethyl)(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazine-3-carbonyl)phenyl)carbamate (18b). To a solution of 2-((3, 5-dichloro-4-
(5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazine-3-carbonyl)phenyl)amino)
acetonitrile (18a) (53 mg, 139.75 umol) in THF (3 mL) was added DMAP (17.07 mg, 139.75 umol) and B0C2O (274 51 mg, 1.26 mmol, 288 95 uL). The mixture was stirred at 25°C for 5 minutes. The mixture was partitioned between ethyl acetate (10 mL*2) and H20 (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous NaiSOr, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (petroleum ether : ethyl acetate= 1 : 1) to give 18b Ή NMR (400 MHz, CDCI3) d 7 87 - 7 84 (m, 1H), 7 35 (s, 2H), 4 52 (s, 2H), 3 75 (s, 3H), 3.28 - 3 19 (m, 1H), 1.54 (s, 9H), 1 .29 (d, I = 7.0 Hz, 6H).
[0329] (Z)-tert-butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-(5-isopropyl-l- methyl-6-oxo-l,6-dihydropyridazine-3-carbonyl)phenyl)carbamate (18c). To a solution of tert-butyl (cyanomethyl)(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)carbamate (18b) (32 mg, 66 76 umol) in DMF (3 ml.) was added NH2OH.HCI (37.11 mg, 534.05 umol) and NaOAc (27.38 mg, 333.78 umol). The mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL) and H2O (3 mL) twice. The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSCfi, filtered and concentrated in vacuum to give 18c. The product was used directly for the next step without further purification.
[Q330] tert-butyl (3,5-dichloro-4-(5-isopropyl-l -methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (18d). To a solution of (Z)-tert-butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-(5-isopropyl-l- methy]-6-oxo-l,6-dihydropyridazine-3-carbonyl)phenyl)carbamate (32 mg, 62.45 umol) (18c) in THF (3 mL) was added DSC (20.80 mg, 81.19 umol) and TEA ( 12.64 mg, 124.91 umol, 17.39 uL). The mixture was stirred at 60°C for 13 hours. LCMS showed the desired mass. The reaction mixture was extracted with ethyl acetates 20 ml.* 2 and H2O 20 mL*2. The combined organic layers were washed with brine 20 mL, dried over NaiSOr, filtered and concentrated under reduced pressure to give 18d as a yellow solid. Hie crude product was used for the next step without further purification. MS mass calculated for [M+l]+ (C23H25Q2N5O6) required m/z 538.1, LCMS found m/z 438.2/538.2.
[0331] 3-(((3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one (Example 18). A solution of tert- butyl (3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (18d) (22 mg, 40.86 umol) in EtOAc/HCl (2 M, 2 mL). The mixture was stirred at 25°C for 1 hour. LCMS showed desired mass. Hie mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to give Example 18. MS mass calculated for [M+l]+ (CisHnCkNsO-*) required m/z 438.1 , LCMS found m/z 438 2; 'H NMR (400 MHz, MeOD) d 7 86 (s, 1H), 6.78 - 6.71 (m, 2H), 4.32 (s, 21 1). 3.72 (s, 3H), 3.18 ( id. J = 6.8, 13.7 Hz, 1 1 1 ). 1.27 (d, J = 6.8 Hz, 6H).
Scheme D: 0-((4-animo-2,0-dkhlorophenyI)thio)-4-isepropyl~2~methyipyridaz!n~3(2H}~one
Figure imgf000108_0001
[0332] ()-(2,6-dichloro-4-nitrophenyI) dimethylcarbamothioate (19a). To a solution of 2,6- dichloro-4-nitrophenol (1 g, 4.81 mmol) in DMF (20 mL) was added NaH (288.44 mg, 7.21 mmol, 60% purity). Then the mixture was stirred at 20°C for 1 hour. Then and N, N- dimethylcarbamothioyl chloride (950.81 mg, 7.69 mmol) was added in the mixture. Hie mixture was stirred at 20°C for 16 hours. The mixture was extracted with EtOAc (20 mL*2).
The combined organic layer was washed with brine (15 mL), dried over NaiSCK filtered and concentrated in vacuum. The residue was purified by column silicagel chromatography (petroleum ether : ethyl acetate== 20: 1 to 5: 1) to give 19a. ‘HNMR (400MHz, CDCb) d 8.28 (s, 2H) 3.50 (s, 3H) 3.44 (s, 3H).
[0333] S-(2,6-dieh!oro-4-mtrophenyl) dimethylcarbamothioate (19b) 0-(2,6-dichloro-4- nitrophenyl) dimethylcarbamothioate (19a) (0.9 g, 3.05 mmol) was added in a flask and stirred at 200°C for 4 hours. LCMS showed desired MS Tire mixture was cooled to 20°C to give 19b. The crude reaction product was used directly in next step. 'Ή NMR (400 MHz, DMSO-c/e) d 8.44 (s, 2H) 3.13 (br s, 3H) 2.95 (br s, 3H).
[0334] 0-(2,6-dkhIoro-4-nitrophenyl) dimethylearbamothioate (19c). To a solution of S- (2,6-dichloro-4~nitrophenyi) dimethylearbamothioate (19b) (0.8 g, 2 71 mmol) in AcOH (10 mL), 2-propanol (20 mL) and H2O ( 10 mL) was added Fe (1.06 g, 18.97 mmol). Then the mixture was stirred at 95°C for 2 hours. The mixture was cooled to 20°C, and saturated NaHCOs solution was added in the mixture until pH= 8~9 and filtered. Then the filtrate was concentrated in vacuum to remove most solvent. Then the residue was extracted with H2O (50 mL) and EtOAc (50 mL*2). The combined organic layer was dried over NazSOy filtered and concentrated in vacuum to give 19c. The product was used directly in next step. !HNMR (400 MHz, ( DC i d d 6.73 (s, 2H) 3.98 (br s, 21 !) 2.90 - 3 25 (m, 6! !).
[0335] 4-amino~2,6~dich!orobenzenelhio! (19d). To a solution of 0-(2,6-dichloro-4- nitrophenyl) dmietliyicarbamothioate (19c) (0.7 g, 2.64 mmol) m EtOH (20 mL) was added KOI 1 (3 M, 20 mL). Then the mixture was refluxed at l00°C for 16 hours. LCMS showed the reaction was completed. The mixture was cooled to 20°C, and HCl solution (1M) was added in the mixture until pH= 2~3. The mixture was extracted with EtOAc (50 mL). Hie organic layer was dned over NarSQr, filtered and concentrated m vacuum to give 19d. Hie product was used directly m next step. T! NMR (400 MHz, CDCb) d 7.27 (s, 2H) 6.70 (s, 2H) 4.23 (s, 1H) 3 70 (hr s, 2H).
[0336] 3,5-dichloro-4-((6-chIoro-5-isopropylpyridazin-3-yI)thio)aoiIme (19e). To a solution of 4~amino-2,6-dichlorohenzenethiol (19d) (520 mg, 2.68 mmol) and 3,6~dichloro~4- isopropylpyridazine (la) (51 1 .90 mg, 2 68 mmol) in DMSO (15 mL) was added K2CO3 (1.11 g , 8.04 mmol). Then the mixture was stirred at 95°C for 16 hours. After coolimg to room temperature, the mixture was was diluded with water (50 mL) and extracted with EtOAc (50 mL*2). The combined organic layer was washed with brine (30 mL), dried over NaiSOr, filtered and concentrated in vacuum. The residue was purified by Prep-TLC (petroleum ether ; ethyl acetate ==2: 1) to give 19e. !H NMR (400 MHz, CDCb) d ppm 7.01 (s, 1H) 6.78 (s, 2H) 4.10 (br s, 2H) 3.14 - 3.27 (m, 1 1 !) 1.23 (d, J = 6.84 Hz, 6H).
[Q337] 2-(3,5-dichIoro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3- yl)thio)phenyl)isoind-oline-l,3-dione (19f). To a mixture of 3,5-dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl)thio)aniline (19e) (1 g, 2.87 mmol) and isobenzofuran-l,3-dione (424.79 mg, 2.87 mmol) in HOAc (8 mL) was added NaOAc (1.18 g, 14.34 mmol). The mixture w¾s stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solid was dissolved in water and the pH was adjusted to 9 with NaHCOn (10 mL). Then the mixture as partitioned with ethyl acetate (30 mL) twice. The combined organic phase was washed with brine (10 mL* 3), dried with anhydrous NaiSCh, filtered and concentrated in vacuum. The solid was stirred in ethyl acetate (10 mL) and petroleum ether (50 mL), then filtered and dried to give 19f. The product was used directly for the next step without further purification. Ή NMR (400 MHz, DMSO) d 8.00 - 8.05 (m, 2 H) 7.93 - 7.97 (m, 2 H) 7.84 (s, 2 H) 7.32 (d, j = 0.86 Hz, 1 H) 3.01 (quin, J = 6.79 Hz, 1 H) 1.14 (d, J = 6.85 Hz, 6 H)
[Q338] 2~(3,5~dkMoro-4~((5-isoprepyt-l-methyl~6~oxo~l,6-diilhydropyridazi ~3~yI}thiio)- phenyI)isoindoI e-l,3-dione (19g). A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin~3-yi)thio)pheny3)isoind-oline-L3-dione (19f) (955 mg, 2.07 mmol) in DMF- DMA (8 mL) was stirred at 120°C for 16 hr. The mixture was concentrated in vacuum to give a residue. The residue was partitioned between ethyl acetate (10 mL) and H2O (3 mL) twice. Hie combined organic phase was washed with brine (5 niL*3), dried with anhydrous NaiSCL, filtered and concentrated in vacuum to give 19g The product was used directly for the next step without further purification. MS mass calculated for [M+l]+ (C22H17CI2N3O3 S) required m/z 474.0, Li MS found m/z 474.0.
[Q339] 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19h). A mixture of 2-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)thio)-phenyl)isoindoline-l,3-dione (19g) (980 mg, 2.07 mmol) and bntan-1 -amine (453.29 mg, 6.20 mmol, 612.55 uL in MeOH (2 mL) was stirred at 70°C for 1 hour. The mixture was concentrated in vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether : ethyl acetate=i : l ) to give 19h. MS mass calculated for [M+l ]
(C14H15CI2N3OS) required m/z 344.0, LCMS found m/z 344.1; ’Ή NMR (400 MHz, CD3OD) d 6.85 (d, J = 0.73 Hz, 1 H) 6.80 (s, 2 H) 3.64 (s, 3 H) 3.09 (qd, J = 7.01, 6.48 Hz, 1 H) 1.12 (d, J = 6.97 Hz, 6 H).
Example 19: 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)suIfonyl)phenyl)amino)methyl)-l,2,4-oxadiazoI-5(4H)-one
Figure imgf000111_0001
[0340] 2 ((3,5-dic Soro~4-((S~isopropyl-l-met yS-6-oxo-l,6 dihydropyridazin-3- y!)lhio)phenyl)amino)acelonitrile (19i). To a solution of 6-((4-amino-2,6- dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19h) (420 mg, 1.22 mmol) in ACN (3 mL) was added 2-bromoacetonitrile (731.69 mg, 6.10 mmol, 406.49 uL), K2CO3 (337.23 mg, 2.44 mmol) and Nal (365.75 mg, 2.44 mmol). The mixture was stirred at 100°C for 16 hours. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (10 mL*3). The combined filtrates were concentrated to dryness to give a residue. The residue was purified by preparative TLC (petroleum ether : ethyl acetate=l : 1) to give 191 MS mass calculated for [M+l]+ (CieHieChNrOS) required rn/z 383.3, LCMS found m/z 383.0; Ή NMR (400 MHz, CDCb) 6 6.82 (s, 2H) 6.79 (d, J = 0.73 Hz, i l l) 4.39 (d, J = 6.85 Hz, 1H) 4.12 - 4 24 (m, 21 1) 3.77 (s, 1H) 3.67 (s, 31 1) 3.11 - 3.20 (m, 1H) 1.16 (d, J = 6.85 Hz, 61 1).
[0341] tert-buty! (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazm-3-yi)ihio)phenyl)carbamate (19j). To a solution of 2-((3,5-dichloro-4-((5- isopropyl-l-methyl-6-oxo-i,6-dihydropyridazm~3-yl)tliio)phenyl)amino)acetonitrile (191) (420 mg, 1.10 mmol) in THF (3 mL) was added DMAP (133.87 mg, 1.10 mmol) and B0C2Q (717.45 mg, 3.29 mmol) at 25°C Tire mixture was stirred at 25°C for 20 minutes. The mixture was partitioned between ethyl acetate 10 mL and H2O 3 mL twice. Hie combined organic phase was washed w ith brine (5 mL*3), dried with anhydrous NaiS04, filtered and concentrated in
no vacuum. The residue was purified by prep-TLC (SiOi, petroleum ether : ethyl acetate = 3: 1) to give 19j . Ή NMK (400 MHz, CDCb) d 7.46 (s, 21 1 ) 6.84 (s, i l l ) 4.53 (s, 21 1) 3.64 (s, 3H) 3.18 icli. I = 13.66, 6.80 Hz, 1H) 1.53 (s, 9H) 1.18 (d, J = 6.85 Hz, 6H).
[0342] (Z)-tert-bulyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-l- methyl-6~oxo-l,6-dihydropyridaz!5i-3-y!)thio)phenyl)carbaniate (19k), To a solution of tert- butyl (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)thio)phenyl)carbamate (19j) (250 mg, 517.16 umol, 1 eq) in DMF (3 mL) -was added
NH2OH.HCI (2.87.50 mg, 4.14 mmol, 8 eq) and NaOAc (339.38 mg, 4.14 mmol, 8 eq) at 25°C. The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with water (5 mL) and extracted with ethyl acetate (15 mL, twice). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSOi, filtered and concentrated in vacuum to give a residue.
Hie residue was purified by prep-TLC (S1O2, petroleum ether : ethyl acetate ::: 1 : 1) to give 19k. ¾ NMR (400 MHz, CDCb) d 7.99 (s, 1H) 7.60 (s, 2H) 7.05 (d, I = 0.66 Hz, 1H) 4.31 (s, 2H) 3.59 (s, 31 1) 3.11 (dt, J = 13.67, 6 84 Hz, 1 1 1) 1.49 (s, 9H) 1.17 (d, J = 7.06 Hz, 6H).
[Q343] tert-butyi (3,5-d!chSoro-4-((S~isopropyl-l -methyI-6-oxo-l ,6-dihydropyridazin-3- yI)thio)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-y!)methyl)carbamate (191). To a solution of (Z)-tert-butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4- ((5-isopropyi-l-methyl-6-oxo-i,6-dihydropyridazin-3-yl)thio)phenyl)carbamate (19k) (220 mg,
425.99 umol) in THF (4 mL) was added DSC (141.86 mg, 553.79 umol) and TEA (86.21 mg,
851.99 umol, 118.59 uL). The mixture was stirred at 60°C for 16 hours. The mixture was concentrated in vacuum to give a residue. The residue was purified by prep-TLC (S1O2, DCM: MeOH = 10: 1 ) to give 191. MS mass calculated for [M+l]+ (C22H25CI2N5O5S) required m/z 542 4, LCMS found m/z 542.1; Ή NMR (400 MHz, CD3OD) d 7.63 (s, 2H) 7.04 (d, J = 0.73 Hz, 1H) 4.82 (s, 2H) 3.58 (s, 3H) 3.07 - 3.15 (m, 1H) 1.48 (s, 9H) 1.16 (d, J = 6.85 Hz, 6H).
[0344] tert-butyl(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)sulfonyl)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (19m). To a solution of tert-butyi (3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazin-3~ yl)thio)phenyl)((5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yi)methyl)carbamate (191) (20 mg, 36.87 umol) in DCM (2 mL) was added rn-CPBA (37.43 mg, 184.35 umol, 85% purity). Then the mixture was stirred at 60°C for 48 hours. The reaction mixture was quenched by addition NaiSCh (23 mg) at 20°C and was stirred for 30 minutes. Then the mixture was concentrated under reduced pressure to give 19m. MS mass calculated for [M+] ]+ (C22H25CI2N5O7S) required m/z 574.4, LCMS found m/z 574.1. The product was used directly for the next step without further purification.
[Q345] 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)sulfonyl)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one (Example 19). A solution of tert-butyl (3,5-dichloro-4-((5-isopropyl-l -methyl-6-oxo-1 ,6-dihydropyridazin-3- yl)sulfonyl)phenyl)((5-oxo-4, 5-dihydro- 1 ,2,4-oxadiazol-3-yl)methyl)carbamate (19m) (20 rng, 34.82 nmol) in HCl/EtOAc (4 M, 2 mL) wus stirred at 20°C for 2 hours. The mixture was concentrated in vacuum to give a residue. The residue was purified by Prep-HPLC (column: Luna C 18 100*30 5u; mobile phase: [water (0.04%HCl)-ACN]; B%: 20%-50%,l lmin) to give Example 19. MS mass calculated for | M ! | (CnHnCLNsOSs) requires m/z 474.3, LCMS found m/z 474 0; 1 IN M R (400 MHz, CDsOD) d 7.74 (s, 1 1 1} 6.83 (s, 2H) 4 38 (s, 21 !) 3.72 (s, 3H) 3.13 (br d, 1 = 1 71 Hz, 1H) 1.24 (d, J = 6.85 Hz, 6H).
Example 20: N-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)suIfonyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000113_0001
[Q346] N-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)thio)ph-enyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (20a). To a mixture of 6- ((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19h) (20 mg, 58.10 umol) in DCM (5 mL) wus add TEA (29.39 mg, 290 48 uml, 40 43 uL) and 5-oxo-4H- l,2,4-oxadiazole-3-carbonyl chloride (4e) (8.63 rng, 58.10 umol), the mixture was stirred at 25°C for 0.2 hours. The reaction mixture was partitioned between H2O (5 mL) and EtOAc (5 mL). The organic phase wus separated, washed with brine (5 mL*3), dried over NaiSCfi, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 20a. MS mass calculated for [M+l (CnHisChNsOrS) required m/z 456.0, LCMS found m/z 456.1; >H NMR (400 MHz, CD3OD) d 7.94 - 8.14 (m, 2H) 7.07 (s, 1H) 3.52 - 3 64 (m, 3H) 3 05 - 3.18 (m, 1H) 1.17 (d, I = 6.85 Hz, 6H).
[0347] N-(3,5-dichloro~4-((5-isopropyI~l-methyl-6-oxo-l,6-dihydropyridazin-3- yI)sulfooyl)-phenyS)-5-oxo-4,S-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 20). The mixture of N-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)thio)ph- enyl)-5-oxo-4, 5-dihydro-1 , 2, 4-oxadiazole-3-carboxamide (20a) (8 mg, 17 53 umol) in DCM (1 mL) was added MCPBA (21.36 mg, 105.19 umol, 85% purity), the mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Hie residue was purified by Prep-HPLC (aqueous acetonitrile w/ TFA) to give Example 20. MS mass calculated for [M+l]+ (CnHisCliNsOeS) required m/z 488.0, LCMS found m/z 488.1; >HNMR (400 MHz, DMSO) d 11.40 - 11.66 (m, 1 H) 8.09 - 8.13 (m, 2 H) 7.72 - 7.75 (m, 1 H) 3.62 - 3.65 (m, 3 1 1) 3.08 - 3.11 (m, 1 H) 1.16 - 1.21 (m, 6 H).
E: 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazin-3(2H)-one (21e)
Figure imgf000114_0001
[Q348] 3,6-dichloro-4-cyclopropylpyridazine (21a). H2SO4 (9.88 g, 100.69 mmol) was added to a solution of 3,6-dichloropyridazine (5 g, 33.56 mmol), cye!opropanecarboxylie acid (2.89 g, 33.56 mmol) and AgNCh (5.70 g, 33.56 mmol) in H2O (100 mL) at 60°C, then ammonium persulfate (22.98 g, 100.69 mmol) in H2O (100 mL) was added to the mixture at 70°C, the resulting mixture was stirred at 70°C for 30 minutes The mixture was extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with brine (100 mL), dried over Na2S04, filtered and concentrated, the residue was purified by MPLC (silica gel, petroleum ether ; ethyl acetate = 5: 1) to give 21 a. 1HNMR (400 MHz, CD3Q) d 6.94 (s, 1H), 2.27 - 2 14 (m, 1H), 1.37 - 1.23 (m, 2H), 0.91 - 0.77 (rn, 2H).
[0349] 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-cyclopropylpyridazm-3- yi)acetonitri!e (21b). To a solution of 3,6~diehloro-4-cyclopropy!pyridazine (21a) (0.4 g, 2.12 mmol) and 2-(4-amino-2,6-dich]orophenyl)acetonitrile (13c) (467.96 mg, 2 33 mmol) in THF (10 mL) was added t-BuOK (1 M, 4.23 mL) drop wise at 60°C, the resulting mixture was stirred at 60°C for 40 minutes. After cooling, the mixture was diluted with ethyl acetate (20 mL), washed with brine (20 mL), the organic phase was dried over Na2S04, filtered and concentrated, tire residue was purified by silica gel chromatography (petroleum ether : ethyl acetate ::: 2: 1) to give 21b. 44 NMR (400 MHz, DMSOde) d 7.00 (s, 1H), 6.71 - 6.68 (m, 2H), 6.46 (s, 1H), 6.02 (s, 2H), 2.22 - 2.14 (m, 1 H), 1.25 - 1.19 (m, 21 1).. 0.88 - 0.75 (m, 2H).
[Q350] 6-(4~amino-2,6-diehlorobenzoyl)-4-cydopropyIpyridazin~3(2H)-one (21c). To a solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-cyclopropylpyridazin-3-yl)acetonitrile (21b) (365 mg, 1.03 mmol) in dioxane (5 mL) and H20 (10 mL) was added KOH (1.16 g, 20.64 mmol). The mixture was stirred at 100°C for 16 hours under O2. LCMS showed one main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with aqueous HC1 2M to ajust the pH=5-7 and extracted with EtOAc (20 mL * 4). The combined organic layers were washed with brine 20 mL, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give 21c. MS mass calculated for [M+l]+( C14H11CI2N3O2) required m/z 324.0, LCMS found m/z 324.1.
[0351] 6-((4-amino-2,6-dichlorophenyI)(hydroxy)methyl)-4-cydopropyIpyridazin-3(2H)- one (21d). To a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-cyclopropylpyiidazin-3(2H)-one (21c) (100 mg, 308.49 umol) in MeOH (5 mL) was added NaBHi (116.70 mg, 3.08 mmol) at 0°C. The mixture was stirred at 15°C for 16 hours. LCMS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (5 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na SOy filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (S1O2, ethyl acetate: petroleum ether = 2: 1, TLC) to give 21d, MS mass calculated for [M+l]+ (CMH13CI2N3O2) required m/z 326.1, LCMS found m/z 326.1;’Ll NMR (400 MEIz, DMSO-de) S 12.58 (s, 1H), 7.16 (s, 1H), 6.54 (s, 2H), 6 07 - 6.05 (m, 1H), 6.02 - 6 00 (m, 1H), 5.64 (s, 2H), 2.12 - 2.07 (m, 1H), 1.01 ( hr dd, J = 2.8, 8.5 Hz, 21 1). 0.81 (br t, J = 6.0 Hz, 21 1).
[Q352] 6-(4-amino-2,6-dichlorobenzyI)-4-cydopropySpyridazin-3(2H)-one (21e). To a solution of 6-((4-amino-2,6-dichlorophenyi)(hydroxy)methyl)-4-cyciopropy3pyridazin~3(2H)- one (21 d) (50 mg, 153.29 umol) in TEA (1 mL) and DCE (5 mL) was added EfaSiH (89.12 mg, 766.46 umol). Hie mixture was stirred at 50°C for 6 hours. LCMS showed one main peak the desired MS. The reaction mixture was diluted with saturated NaHC03 (5 mL) and extracted with DCM (10 mL * 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue.
The residue was purified by prep-TLC (Si02, ethyl acetate: petroleum ether = 2: 1; TLC) to give 21e. MS mass calculated for [M+l]+ (C14H13CI2N3O) required m/z 310.0, LCMS found m/z 310.1; 1H NMR (400 MHz, CDCb) d 10 39 (br s, 2H), 6.68 (s, 2H), 6.64 (s, 1H), 4.10 (s, 2H), 2.19 - 2.14 (m, 1H), 1.12 - 1.06 (rn, 2H), 0.85 - 0.79 (m, 2H).
Example 21: N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)-5-oxo-4, 5- dihydro-1, 2, 4-oxadiazole-3-carboxamide
Figure imgf000116_0001
[0353] N-(3,5-dich!oro-4-((5-cyc!opropyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 21), To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazin-3(2H)-one (21e) (16 mg, 51.58 umol) in DCM (2 ml,) was added TEA (15.66 mg, 154.75 umol) and 5-oxo-4H-l,2,4- oxadiazole-3-carhonyl chloride (4e) (11.49 mg, 77.37 umol). The mixture was stirred at 25°C for 0.5 hours. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (1 OmM NH4HC03)-ACN]; B%: 2Q%-40%, 10 min) to give Example 21. MS mass calculated for [M+l] + ( C17H13Q2N5O4) required m/z 422.0, LCMS found m/z 422.0; 1 1 NMR (400 MHz, CD3OD) d 7.86 (s, 2H), 6.88 (s, i l l). 4.23 (s, 2H), 2.15 - 2.06 (m, M l ). 1.10 - 1.04 (m, .'l l). 0.85 - 0.79 (m, 2H). Example 22: N-(3,5-dichloro-4-((5-cyclopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carboxamide
Figure imgf000117_0001
[0354] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)isoindoline-l,3-dione (22a). To a solution of 6-(4-amino-2,6- dichlorobenzyl)-4-cyclopropylpyridazin-3(2H)-one (21e) (44 mg, 141.85 umol) in AcOH (3 mL) was added isobenzofiiran-l,3-dione (22.06 mg, 148.95 umol). The mixture was stirred at 120°C for 2 hours TLC showed one new spot was formed. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water 2 mL and added saturated aqueous NaHCCL to modified pH=9~lO. The suspension was extracted w ith EtOAc 20 mL (5mL*4), the combined organic layers were dried over anhydrous NarSCb, filtered and concentrated under reduced pressure to give 22a was used into the next step without further purification as light yellow oil. MS mass calculated for [M-t-lJ^CzzHisCbAMT) required m/z 440.1, 1 (MS found m/z 440.1.
[0355] 2-(3,5-dichloro-4-((5-cyclopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yI)methyl)phenyl)isoindoline-l,3-dione (22b). A solution of 2-(3,5-dichloro-4-((5- cyciopropyl-6-oxo-l,6~dihydropyridazin-3~yl)methyl)phenyl)isoindoiine-l,3~dione (22a) (70 mg, 158.99 umol) in DMF-DMA (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 10G°C for 3hr under N2 atmosphere. LCMS showed 22a was consumed completely and one main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove DMF-DMA, and then the mixture was to give a residue. The residue was diluted with HrO 5 mL and extracted with EtOAc 20 mL (5 mL * 4). The combined organic layers were washed with brine 5 mL, dried over anhydrous NaiSQr, filtered and concentrated under reduced pressure to give 22b was used into the next step without further purification as a light yellow gum. MS mass calculated for [M+l]+ (C23H17CI2N3O3) required m/z 454.1, LCMS found m/z 454.0.
[0356] 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropyl-2-methylpyridazin-3(2H)-one (22c), To a solution of 2-(3,5-dichloro-4-((5-cyclopropyl-l-methyl-6-oxo-l ,6~dihydropyridazin-3~ yl)methy])phenyl)isoindoline-l ,3-dione (22b) (100 mg, 154.08 umol) in MeOH (3 mL) was added N-butylamine (33.81 mg, 462.24 urnol). The mixture was stirred at 70°C for 0.5hr. LCMS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove solvent. Tire residue was purified by prep-TLC (S1O2, petroleum ether : ethyl acetate; TLC) to give 22c. MS mass calculated for [M tTj CisHisCbTLi)) required m/z 324.1, LCMS found m/z 324.0; ¾ NMR (400 MHz, CDCI3) d 6.70 - 6.65 (m, 2H), 6.48 (s, 1H), 4.07 (s, 2H), 3.79 (br s, 2H), 3 74 (s, 3H), 2.24 - 2.13 (m, i l l). 1.07 - 0 99 (m, 2H), 0.75 - 0.66 (m, 2H).
[Q357] N-(3,5-dichloro-4-((5-cyclopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)methyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 22). To a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-c}7clopropyl-2-methylpyridazin-3(2H)-one (22c) (10 mg, 30.84 umol) in DCM (2 mL) was added TEA (9.36 mg, 92.53 umol, 12.88 uL) and 5- oxo-4H-l,2,4-oxadiazole-3-carbonyl chloride (4e) (6.87 mg, 46.27 umol). The mixture was stirred at 25°C for 0.5 hours. LCMS showed tire desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was checked by HPLC and purified by prep-HPLC (column: Waters Abridge 150*25 5u; mobile phase: [water (lOmM NH4HC03)-ACN] ; B%: 5%-35%, 14 min) to give Example 22 as a white solid. MS mass calculated for [M+l]+( C M i A'i.-NA) ;) required m/z 436.0, LCMS found m z 436.0; 1 ! N MR (400 MHz, CD3OD) d 7.87 (s, 2H), 6.85 (s, 1H), 4.24 (s, 2H), 3.65 (s, 31 13. 2.20 - 2.09 (m, 11 1). 1.1 1 - 1 04 (m, 2H), 0.83 - 0.75 (m, 2EI).
Example 23: N-(3,5-dichloro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3- yl)methyl)phenyl)-5-oxo-4, 5- dihydro-1, 2, 4-oxadiazole-3-carboxamide
Figure imgf000119_0001
[Q358] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)-5- oxo-4,S-dihydro-l,2,4-oxadiazole-3-carboxamkle (Example 23). To a solution of 3-(4-amino- 2,6-dichloro-phenoxy)-5-isopropyl-lH-pyridazin-6-one(8b) (13.7 g, 43.61 mmol) in THF (140 mL) was added TEA (13.24 g, 130 82 mmol) and 5-oxo-4H-l,2,4-oxadiazole-3-carbonyl chloride (4e) (9.71 g, 65.41 mmol). The mixture was stirred at 20°C for 0.5 hours. LCMS showed a peak with the desired MS. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was triturated w ith EtOAc (100 mL) at 80 °C for 30 min, and then cooled to 20°C. The suspension was filtered and filter cake was washed with EtOAc (5 mL*3) and concentrated to dryness to give Example 23. MS mass calculated for [M+lfC C16H13CI2N5Q5) required m/z 426.0, LCMS found m/z 426.0; !H NMR (400 MHz, CD3OD) d 7.92 (s, 2H), 7.33 (d, = 0.9 Hz, 1H), 3.21 - 3.13 (m, 1H), 1 .29 (d, J= 6.8 Hz, 6H).
Example 24: N-(6-chloro-7-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazm-3-yl)oxy)- 2,3-dihydro-lH-inden-4-yI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carboxamide
Figure imgf000120_0001
[0359] 6-chloro-7-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-indan-4-amine i
Figure imgf000120_0002
amino-5-chloro-indan-4-ol (0.39 g, 2.12 mmol), 3,6-dichloro-4-isopropyl-pyridazine (la)
(405.77 mg, 2.12 mmol), Cul (40.45 mg, 212.38 umol) and K2CO3 (440.28 mg, 3.19 mmol) in DMA (15 rnL) was de-gassed with N2 and then heated to l00°C for 16 hours under N2. LCMS showed the reaction was completed, and desired MS was detected. The mixture was filtered through a pad of celite, washed with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 ml,), dried over NazSOi, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 3: 1) to give 24a. MS mass calculated for [M+l^CieHnClilShO) required m/z 338.1 , LCMS found m/z 338.1.
T-INMR (400 MHz, DMSO-de) d 7.53 (s, 1H), 6.56 (s, IH), 5.15 (br s, 2H), 3.14 (td, I = 6 8,
13.6 Hz, I I I ). 2.68 (br t, J = 7.3 Hz, 2H), 2.60 (br t, J = 7.4 Hz, 21 1). 2.03 - 1.95 (m, 2H), 1.27 (d, J = 6.7 Hz, 6H).
[0360] 2-[6-chloro-7-[(5-isopropyl-6-oxo-lH-pyridazin-3-yl)oxy]indan-4-yl]isoindoline- 1,3-dione (24b). To a mixture of 6-chloro-7-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-indan-4- amine (24a) (120 mg, 354.79 umol ) and isobenzofuran-l,3-dione (52.55 rng, 354.79 umol) in NaOAc (101.87 mg, 1.24 mmol) was added AcOH (1 rnL). Hie mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solid was dissolved in water and the pH was adjusted to 9 with NaHCC (10 niL). Then the mixture was partitioned with Ethyl acetate (30 mL). Twice. The combined organic phase was washed with brine (10 mL*3), dried with anhydrous NaiSO , filtered and concentrated in vacuum to give 24b. The product was used directly in next step without further purification. MS mass calculated for [M-H]+ (C24H20CIN3Q4) required m/z 450.1, LCMS found m/z 450.2.
[0361] 2-[0-chloro~7-(5-isopropy]!-l~methyl!-6-Gxo~pyridazm-3-y!)&xy~mdan-4- yl] isoin do!ine-l,3-dione (24c). A solution of 2-[6-chloro-7-[(5-isopropy]-6-oxo-lH-pyridazin- 3-yl)oxy|indan-4-yl]isoindoline-l,3-dione (24b) (150 mg, 333.42 nmol) in DMFDMA (2 mL) was stirred at 80°C for 2 hours. The mixture was concentrated in vacuum. The residue was partitioned between ethyl acetate 10 mL and H2O 3 ml. twice. The combined filtrate was washed with brine (20 mL), and the organic phase was concentrated to give 24c, the crude product was used for the next step directly. MS mass calculated for [M+l]+ (C2.-3H22CIN3O4) required m/z 464.1, LCMS found m/z 464.2.
[0362] 6-(7-amino-5-chloro-indan-4-yl)oxy-4-isopropyl-2-methyl-pyridazin-3-one (24d).
A mixture of 2-[6-chloro-7-(5-isopropyl-l-methyl-6-oxo-pyridazin-3-yl)oxy-indan-4- yl]isoindoline-l,3-dione (24c) (100 mg, 215.56 umol) and N-butyiamine (15.77 mg, 215.56 umol) in MeOH (2 mL) was stirred at 25°C for 1 hour. The mixture was concentrated in vacuum. Tire residue was purified by prep-TLC (S1O2, petroleum ether /ethyl acetate= 1 : 1 ) to give 24d. MS mass calculated for [M+l]+ (C17H20CIN3O2) required m/z 334.1, LCMS found m/z 334.1.
[0363] N-(6-chloro-7-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-2,3- dihydro-lH-inden-4~yl)-5-oxo-4, 5- dihydro-1, 2, 4-oxadiazole- 3-carboxamide
(Example 24). To a solution of 24d (10 mg, 29.96 umol, 1 eq) THF (5 mL) was added TEA (9.09 mg, 89.87 umol, 12.51 uL) and 5-oxo-4H-l,2,4-oxadiazole-3 -carbonyl chloride (4e) (6.67 mg, 44.94 umol). Tire mixture was stirred at 25°C for 0.5 hours. Tire reaction mixture was quenched by addition MeOH (1 mL) at 25 °C, and then concentrated under reduced pressure to give a residue. The residue was checked by HPLC and then was purified by Prep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.04%HCl)-ACN]; B%: 35%-60%, 12min) to give Example 24. MS mass calculated for [M+l]+ (C20H20CIN5O5) required m/z 446.1 , LCMS found m/z 446.2; ¾ NMR (400 MHz, CD3OD) S 7.55 (s, 1H), 7.27 (s, 1H), 3.50 (s, 3H), 3.20 - 3.12 (m, 1H), 2.94 (br t, J = 7.4 Hz, 2H), 2.87 (br t, J = 7.3 Hz, 2H), 2.17 - 2.12 (m, 2H), 1.27 (d, J =
Figure imgf000121_0001
yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000122_0001
[0364] 3,5-dichSoro~4-((6-chSoro-5-cydopropylpyridazin-3~yS)oxy)ani!ine (25a),
3,6-dichloro-4-cyclopropyl-pyridazine ( 1 g, 5.29 mmol) (21a), 4-amino-2,6-dichloro-phenol (941.67 mg, 5.29 mmol), K2CO3 (1.10 g, 7.93 mmol) and Cul (201.49 mg, 1.06 mmol) in DMA (5 ml.) was de-gassed and then heated to 100°C for 16 hours under N2. Solids were filtered off and to the filtrate was added water (20 ml.) and was extracted with ethyl acetate (15 mL*2). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate= 5: 1) to give 25a. MS mass calculated for [M+l ] (C13H10Q3N3O) required m/z 330 0, LCMS found m/z 329.9/331.9;
[0365] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)-5- oxo~4,5~dihydro-l,2,4-oxadiazo!e-3~carboxamide (25b), To a solution of 5-oxo-4,5-dihydro- l,2,4-oxadiazole-3-carboxylic acid (1 1.80 mg, 90.75 umo) in THF (2 mL) was added one drop DMF, then (COCl)2 (11.52 mg, 90.75 umol, 7.94 uL, 1.5 eq) was added at 0°C, the mixture was stirred at 25°C for 1 hour, the solution was added to a mixture of 3,5-dichloro-4-((6-chloro-5- cyclopropylpyridazin-3-yl)oxy (aniline (25a) (20 mg, 60.50 umol) and TEA (18.37 mg, 181.50 umol, 25.26 uL) in DCM (3 mL) at 25°C, the resulting mixture was stirred at 25°C for 30 minutes. The mixture was concentrated, the residue was purified by prep-TLC
(dichloromethane: methanol= 10: 1) to give 25b. MS mass calculated for [M+l]÷
(C16H10CI3N5O4) required m/z 442.0, LCMS found m/z 442.0.
[0366] N-(3,5-dichloro-4-((5-cydopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)-5- oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 25). A mixture of N-(3,5- dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-i,2,4- oxadiazole -3 -carboxamide (25b) (30 mg, 67.78 umol) and NaOAc (33.36 mg, 406.65 umol) in HOAc (3 mL) was heated to 1 !Q°C for 16 hours. The mixture was concentrated. -The residue was purified by prep-HPLC (neutral) to give Example 25. MS mass calculated for [M+l ]+ (CieHuChNsOs) required m/z 424.2, LCMS found rn/z 424.2
Figure imgf000123_0001
d
7.92 (s, 2H), 7.03 (s, 1H), 2.28 - 2.18 (m, 1H), 1.23 - 1.14 (m, 2H), 1.04 - 0.94 (m, 2H).
Example 26: N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000123_0002
Example 26
[0367] 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)- one (26a). To a suspension of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl- pyridazin-3-one (le) (20 g, 60.94 mmol) in CLLCN (200 rriL) and THF (60 mL) under a nitrogen atmosphere was added NaHCOi (15.36 g, 182.82 mmol). To the resulting solution was added Select F (21.59 g, 60.94 mmol) by portion wise addition over 30 min. The mixture was stirred at 20°C for 16 hours. The reaction mixture was partitioned between H2O 200 mL and EtOAc 300 mL. The organic phase was separated, washed with brine (100 mL), dried over NaiSCh, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether /ethyl acetate=4/l to 1/1 ; TLC) to give 26a. MS mass calculated for [M+ l]+ (Ci4Hi4Cl2FN302) required m/z 346.0, LCMS found m/z 346.0; !HNMR (400 MHz, CDCb) d 7.02 (s, 1H), 6.80 (d, I = 8.8 Hz, 1H), 3.89 (br s, 2H), 3.53 (s, 3H), 3.24 (quind, J = 6.8, 13.5 Hz, 1H), 1.26 (d, I = 6 8 Hz, 61 1).
[0368] N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l, 2, 4-oxadiazole- 3-carboxamide (Example 26). To a solution of 6-(4-amino-2,6-dichloro-3 -fluoro-phenoxy)-4-isopropyl-2-methyl-pyridazin-3 -one (26a) (13 g, 37 55 mmol) in THF (130 mL) was added TEA (1 1.40 g, 1 12.66 mmol) and 5-oxo- 4H-l ,2,4-oxadiazole-3-carbonyl chloride (4e) (8.37 g, 56.33 mmol). The mixture was stirred at 20°C for 0.5 hours. LCMS showed a peak with the desired MS. Hie mixture was diluted with 1M HC1 to modified pH 6-7 and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with brine 150 mL, dried over anhydrous NarSOi, filtered to give a light yellow liquid The light yellow liquid was concentrated under reduced pressure to remove solvent and until the solid was dissolved out. The mixture was stirred at 20°C for 1 hour and filtered to give Example 26. MS mass calculated for [M+ 1]+ (Ci 7H14CI2FN5O5) required m/z 458.0, LCMS found m/z 458.0; H N M R (400 MHz, CD3OD) d 8 30 (d, J = 7.5 Hz, 1H), 7 35 (s, 1H), 3 51 (s, 3H), 3 24 - 3.12 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H).
Figure imgf000124_0001
dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one
Figure imgf000124_0002
[Q369] 2-((3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)amino)acetonitrile (27a). To a solution of 6-(4-amino-2,6-dichloro-3- fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (26a) (20 mg, 57.77 umol) in ACN (2 mL) was added 2-bromoacetonitrile (52.26 mg, 435.72 umol, 29.03 uL), K2CO3 (24.09 mg,
174.29 umol) and Nai (26.12 mg, 174.29 umol). The mixture was stirred at i0Q°C for 20 hours. The suspension was filtered through a pad of Celite and tire pad cake was washed with EtOAc (5 mL*3). The combined filtrates were concentrated to dryness to give a residue. The residue was purified by preparative TLC (petroleum ether : ethyl acetate=l : l ) to give 27a. MS mass calculated for [M+l]+ (CieHisCkFNrOr) required m/z 385.2, LCMS found m/z 385.0;’HNMR (400 MHz, CDC! : d 7.04 (s, 1H) 6.81 (d, I = 8 16 Hz, 1H) 4.38 - 4 50 (m, 1H) 4 21 (d, J = 7.06 Hz, 2H) 3.54 (s, 31 1} 3.24 (dt, I = 13.62, 6.75 Hz, 1H) 1.26 - 1.28 (m, 6H).
[Q370] tert-butyl (cyanomethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyI-6- oxo-1, 6-dihydropyridazin-3-yl)oxy)phenyl)carbamate (27b). To a solution of 2-((3,5- dichloro-2-fluoro-4-((5-isopropyl-l -methyl-6-oxo-l ,6-dihydropyridazin-3- yl)oxy)phenyl)amino)acetonitrile (27a) (20 mg, 51.92 umol) in THF (3 mL) was added DMAP (6.34 mg, 51.92 umol) and BociO (33.99 mg, 155.76 umol, 35.78 uL) at 20°C. Hie mixture was stirred at 20°C for 20 minutes. The mixture was concentrated in vacuum to give a residue. The residue was purified by prep-TLC (SiC , petroleum ether : ethyl acetate = 2: 1) to give 27b. MS mass calculated for [M+l ]+ (C21H23CI2FN4O4) required m/z 485.3, LCMS found m/z 485.2;
Ή NMR (400 MHz, CDCb) d 7.43 (br s, 1H) 7.07 (s, 1H) 4.52 (br s, 2H) 3.52 (s, 3H) 3.26 (dt, J - 13.66, 6.92 Hz, 1H) 1.25 - 1.47 (m, 15H).
[0371] (Z)-tert-butyl (2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-2-fluoro-4- ((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)carbamate (27c). To a solution of tert-butyl (cyanomethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)carbaniate (27b) (20 mg, 41.21 umol) in DMF (2 mL) was added NH2OH.HC! (22.91 mg, 329.67 umol) and NaOAc (27 04 mg, 329.67 umol) at 20°C.
Hie mixture was stirred at 80°C for 1 hour. Hie reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate 10 mL and H2O 5 ml. twice. The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSOr, filtered and concentrated in vacuum. Hie residue was purified by prep-TLC (S1O2, petroleum ether : ethyl acetate = 1 : 1) to give 27c. MS mass calculated for [M+l]+ (C21H26CI2FN5O5) required m/z 518.4, LCMS found m/z 518.0.
[0372] tert-butyl (3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)methyl)carbamate (27d). To a solution of (Z)-tert-butyl (2-amino-2-
(hydroxyimino)ethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-i,6-dihydrop- yridazin-3-yl)oxy)phenyl)carbamate (27c) (20 mg, 38.58 umol) in THF (3 mL) was added DSC (12.85 mg, 50.16 umol) and TEA (7.81 mg, 77.17 umol, 10.74 uL). The mixture was stirred at 60°C for 16 hours. Hie mixture was concentrated in vacuum to give a residue. Hie residue was purified by prep-TLC (S1O2, DCM: MeOH = 10: 1 , PI : R: 0.3) to give 27d. MS mass calculated for [M+l]+ (C22H24CI2FN5O6) required m/z 544.4, LCMS found m/z 544.0. [0373] 3-({(3,S~diehloro-2~fSuoro~4 ((5-isopropyl-l-met yS-6-oxo-l,6 dihydropyridazin-3- yI)oxy)phenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one (Example 27), A solution of tert- butyl (3 ,5 -didiioro-2-fluoro-4~((5 -isopropyl- 1 -methy 1-6-oxo- 1 ,6-dihydropyridazin-3 - yl)oxy)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)methyl)carbamate (27d) (8 mg, 14.70 nmol) m HC!/EtOAc (2 mL) was stirred at 20°C for 1.5 hours. The mixture was concentrated in vacuum to give a residue. The residue was purified by Prep-HPLC (column: Luna Cl 8 100*30 5u; mobile phase: [water (0.04%HC1)-ACN]; B%: 30%-60%, l2 nun) to give Example 27. MS mass calculated for [M+l]* (C17H16CI2FN5O4) required m/z 444.2, LCMS found m/z 444.0; ¾ NMR (400 MHz, CDsOD) d 7.27 (s, 1H) 6 91 (d, J = 8.33 Hz, 1H) 4.38 (s, 2H) 3.49 (s, 3H) 3 13 - 3.21 (m, 1 1 1 ) 1.26 (d, J = 7.02 Hz, 6H).
Example 28: N-(4-((5-(tert-butyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-3,5- diehlorophenyl)-5-o o-4,S-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000126_0001
[0374] 4-((5-(tert-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (28a). To a solution of 4-(tert-butyl)-3,6-dichloropyridazine (200 mg, 0.975 mmol) in DMSO (5 mL) was added 4-amino-2,6-dichlorophenol (173.61 mg, 0.975 mmol), K2CQ3 (404.34 mg, 2.93 mmol) and Cul (111.44 mg, 0.585 mmol), the mixture was stirred at 90°C for 16 hours under N2 atmosphere. The solvent was diluted with EtOAc (10 mL) and H2O (10 mL), extracted with EA
(10 mL*2), the organic layer was washed with brine (20 mL*2), dried over with NaiSOr, the organic layer was dried over with NarSCE, concentrated in vacuo to get crude. The crude was purified with Prep-TLC (petroleum ether : ethyl acetate=5: 1 ) to give 28a. MS mass calculated for [M+l ]+ (C14H14CI3N3O) required m/z 346.6, LCMS found m/z 346.6; Ή NMR (400 MHz,
CDCb) d 1.51 (s, 9H), 6.67 (s, 2H), 7.24(s, 1H).
[0375] N-(4-((5-(tert-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5- dihydro~l,2,4-oxadiazoie~3-earboxamide (28b). To a mixture of 4-((5-(tert-butyl)-6~ chioropyridazin-3-yl)oxy)-3,5-dichioroamline (28a) (100 mg, 288.48 mmol) in THF (2 mL), was added TEA (87.58 mg, 865.45 umol), 5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carbonyl chloride (4e) (64.26 mg, 432.73 umol) in DCM (2 mL) was added under Ni atmosphere. The mixture was stirred at 20°C under Ni for 0.5 hours. The mixture was poured into HrO (10 mL) and the resulting mixture was extracted with EtOAc (10 ml,*3), the organic layer was washed with brine (20 mL*2), dried over with NaiSOy filtrated, concentrated in vacuo to get crude 28c. The crude product was used for the next step without futher purification. MS mass calculated for | M 1 1 (C17H14CI3N5O4) required m/z 458.1, LCMS found m/z 458.1.
[0376] N-(4-((5-(tert-butyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5- oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carboxamide (Example 28), To a mixture ofN-(4~((5- (tert-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-l ,2,4- oxadiazole-3 -carboxamide (140 mg, 305.2 ummol) in HO Ac (10 mL), was added NaOAc (125.19 mg, 1.53 mmol). Then the mixture was stirred at 120°C for 16 hours. Tire solvent was removed in vacuo to get crude. The crude was purified with prep-HPLC (CH3CN in H20,
40%). To get Example 28 (9.9 mg, 7.4% yield). MS mass calculated for [M+l]+
(C17H15CI2N5O5) required m/z 440.2, LCMS found m/z 440.2; !H NMR (400 MHz, CD3OD) 6 1.44 (s, 9H), 7.32 (s, 1H), 7 92 (s, 2H).
Example 29 (PI and P2): N-(3,5-dichloro-4-((5-(l-hydroxyethyl)-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-cartaoxamide
Figure imgf000128_0001
[0377] l-(3,6-dichioropyridazin-4-yl)ethanol (29a). To a solution of 3,6-dichloro-l, 2,4,5- tetrazine (500 mg, 3.31 mmol) in Tol. (3 mL) was added but-3-yn~2-ol (278.59 mg, 3.97 mmol). The mixture was stirred at 110°C for 16 hours under sealed tube. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC , petroleum ether : ethyl acetate= 1 : 1 ,TLC) to give 29a. Ή NMR (400 MHz, CDCI3) d 7.82 (d, I = 1.0 Hz, 1H), 5.14 (dq, I = 4.2, 6.3 Hz, 1H), 2.38 (d, J = 3.4 Hz, 1 1 1 ). 1.56 (d, J = 6.4 Hz, 3H).
[0378] 3,6-dichloro-4-(l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (29b). To a solution of l-(3,6-dichloropyridazin-4-yl)ethanol (29a) (300 mg, 1.55 mmol) and DHP (653 68 mg, 7.77 mmol, 710.52 uL) in DCM (10 mL) was added TsOH (13.38 rng, 77.71 umol). The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (S1O2, petroleum ether /ethyl acetate=5: l, according TLC) to give 29b. !H NMR (400 MHz, CDCb) d 7.77 (s, 1H), 7.63 (s, 1H), 5.10 (q, J = 6.5 Hz, i l l). 4.98 (q, I = 6.6 Hz, 1H), 4.81 (br d, J = 4.6 Hz, 11 1). 4.47 (br s, 1H), 3.99 - 3.90 (m, IH), 3.67 - 3.53 (m, 2H), 3.47 - 3.40 (m, IH), 1.95 - 1.55 (m, 12H), 1.53 (d,
1 = 6.4 Hz, 31 1 }. 1.46 (d, J = 6.4 Hz, 3H).
[Q379] 3,5-dichloro-4-((6-chloro-5-(l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3- yl)oxy)aniline (29c). To a solution of 4-anrino-2,6-dichloro-phenol (167.00 mg, 938.13 umol) and 3,6-dichloro-4-(l -((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (29b) (200 mg, 721.64 umol) in DMSO (5 mL) was added K2CO3 (299.21 mg, 2.16 mmol) and Cul (82.46 mg, 432.98 umol) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for
2 hours under N2 atmosphere. 1 (MS detected one main peak with desired MS. The reaction mixture was diluted with H2O 5 mL and extracted with ethylacetate 30 mL (10 mL * 3). The combined organic layers were washed with brine 10 mL, dried over anhydrous NarSOy filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (Si02, petroleum ether : ethyl acetate = 1 : 1, TLC) to give 29c. Ti NMR (400 MHz,
CDCb) d 7.55 (s, 1H), 7.37 (s, 1 H), 6.68 (s, 4H), 5.10 (q, J = 6.6 Hz, 1H), 5.00 (q, J = 6.4 Hz, 1H), 4.90 - 4.85 (m, I I I). 4.52 (t, I = 3.6 Hz, I I I). 3.96 (ddd, I = 3.8, 7.5, 11.2 Hz, 1H), 3.81 (far d, J = 2.4 Hz, 4H), 3.65 (ddd, J = 3.2, 8.0, 11.3 Hz, i l l). 3.61 - 3 54 (m, 1H), 3.47 - 3.40 (m,
IH), 1 .96 - 1.60 (m, 12H), 1 .55 (d, J = 6.5 Hz, 3H), 1.49 (d, I = 6 4 Hz, 3H).
[0380] N-(3,5-dichloro-4-((6-chloro-5-(l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin- 3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazoIe-3-carboxamide (29d). To a solution of 3,5 -dichloro-4-(( 6-chloro-5 -( 1 -((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin -3 -yl)oxy)anil ine (29c) (250 mg, 597.08 umol) in DCM (5 mL) was added TEA (181.26 mg, 1.79 mmol, 249.32 uL) and 5-oxo-4H-l,2,4-oxadiazole-3-carbonyl chloride (4e) (133.00 mg, 895.63 umol). The mixture was stirred at 25°C for 0.5 hours lire reaction mixture was concentrated under reduced pressure to give a residue. Tire residue w¾s purified by prep-TLC (S1O2, DCM: MeOH = 10: 1 , according TLC) to give 29d. MS mass calculated for [ +r iCioE!isCbN Oe required m/z 530.0, LCMS found m/z 529.9.
[0381] l-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-l,2,4-oxadiazole-3- cartaoxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)ethyl acetate (29e). To a solution of N-(3,5-dichloro-4-((6-chloro-5-(l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (29d) (60 mg, 90.44 umol) in AcOH (3 mL) wns added NaOAc (37.09 mg, 452.19 umol). Tire mixture was stirred at 12C)°C for 16 hours. Tire reaction mixture w¾s concentrated under reduced pressure to remove AcOH and then to give 29e was used into the next step without further purification. MS mass calculated for [M+l^CnH iiCkNsO?) required m/z 470.0, LCMS found m/z 470.0. [0382] N-(3,5-dichloro-4-((5-(l-hydroxyethyl)-6-oxo-l,6-dihydropyridazin-3- yi)oxy)phenyi)-5~oxo-4,5-dihydro-l, 2, 4-Qxadiazo!e- 3-carboxamide (Example 29). To a solution of l-(6-(2,6-dichloro-4-(5-oxo-4, 5-dihydro- 1,2, 4-oxadiazole-3-carboxamido)phenoxy)- 3-oxo-2,3~dihydropyridazin-4~y3)ethyi acetate (29 e) (105 mg, 223.30 umo3) in MeOH (3 ml.) and H’O (0.5 mL) was added LiOHTfcO (18.74 mg, 446 60 nmol). The mixture was stirred at 25°C for 1 hour. LCMS detected the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with 6 M HC1 to modified pH = 6- 8 and extracted with EtOAc (5 mL * 4), dried over anhydrous NaiSOr, filtered and concentrated under reduced pressure to give a residue. Tire residue was purified by prep-HPLC (column: Luna Cl 8 100*30 5u; mobile phase: [water (I QmM NH4HC03)-ACN]; B%: l%-40%, 12min) to give Example 29 MS mass calculated for [M+l]+( C :.d I: :( Ί L40.·.) required m/z 428 0,
LCMS found m/z 428 0; !H NMR (400 MHz, DMSO-de) d 12 28 (s, 1H), 1 1 31 (s, 1H), 7.99 (s, 21 i ). 7 40 (d, J = 1.1 Hz, 1H), 5.49 (br s, i l l). 4.70 (q, J = 6 1 Hz, i l l). 1.33 (d, I = 6.4 Hz, 3H).
[0383] (R)-N-(3,5-dichloro-4-((5-(l-hydroxyethyl)-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l, 2,· 4-oxadiazole- 3-carboxamide (Example 29-PI) and (S)-N-(3,5-dichloro-4-((5-(l-hydroxyethyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)-5- oxo-4,5-dihydro-l,2,4-oxadiazo!e-3-carboxamide (Example 29-P2). The N-(3,5-dichloro-4- ((5-(l-hydroxyethyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazole-3-carboxamide (Example 29) was checked and purified by Chiral SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase: [0.1%NH3*H2O MeOH]; B%: 40%-40%, 10mm) to give Example 29-PI and Example 29-P2.
[0384] Example 29-PI: MS mass calculated for ] M 1 1 ( C :d i : :iTVO,-.) required m/z 428.0, LCMS found m/z 428.0; H NMR (400 MHz, DMSO-de) d 12.26 (s, i l l). 10.71 (br s, 1H), 8 06 (s, 2H), 7.39 (d, J = 1.3 Hz, i l l). 5.49 (br d, J = 4.4 Hz, 1H), 4.74 - 4.66 (m, 1H), 1.33 (d, J = 6.6 Hz, 3H).
[0385] Example 29-P2: MS mass calculated for [M+l]+( C15H11 C12N506) required m/z 428.0, LCMS found m/z 427 9; 1 1 N R (400 MHz, DMSO-de) d 12.26 (s, !H), 10 74 (br s,
1H), 8.05 (s, 2H), 7.39 (d, J = 1.3 Hz, 1H), 5.49 (br d, J = 4.4 Hz, 1H), 4.75 - 4.66 (m, 1H), 1.33 (d, J = 6.4 Hz, 3H).
Example 30: N-(4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)meihyl)-3,5- dimethylphenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000131_0001
[Q386] 5-bromo-2-(bromomethyl)-l,3-dimethylbenzene (30a). To a solution of (4-bromo-
2,6-dimethylphenyl)methanoi in DCM (30 mL) was added PPh3 (1.83 g, 6.97 mmol). Then the mixture was cooled to 0-5°C Then CBr4 (2.31 g, 6.97 mmol) was added in the mixture by portions. Then the mixture was stirred at 15°C for 0.5 hours under N? The mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiC , petroleum ether /ethyl acetate = 1/0 to 10: 1,TLC) to give 30a. ¾ NMR (400 MHz, CDCb) d 7.21 (s, 2H) 4.50 (s, 211) 2.39 (s, 6H).
[0387] 2-(4-bromo-2,6-dimethySpheoyl)aceionitrile (30b). To a solution of 5-bromo-2- (bromomethyl)~l,3~dimethylbenzene (30a) (1.26 g, 4.53 mmol) in DMF (30 mL) was added NaCN (244.35 mg, 4.99 mmol) at 15°C. Then the mixture was stirred at 15°C for 16 hours.
Hie mixture was partitioned between Ethyl acetate (50 mL) and NH-iCl aqueous solution (20 mL) twice. The combined organic phase was washed with brine (20 mL 3), dried with anhydrous NarSOy filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether : ethyl acetate = 10: 1 to 3: 1 , TLC) to give 39b. i ! NMR (400 MHz, CD3OD) d 7.28 (s, 2H) 3.79 (s, 2H) 2.38 (s, 6H).
[Q388] 2-(4-bromo-2,6-dimethySpheoyl)-2-(6-chloro-5-isopropySpyridazm-3- yI)acetonitrile (30c). To a solution of 2-(4-bromo-2,6-dimethylphenyl)acetonitrile (30b) (800 mg, 3.57 mmol) and 3,6-dichloro-4-isopropylpyridazine (la) (682.05 mg, 3.57 mmol) in THF (10 mL) was was added t-BuOK (1 M, 7.14 mL, 2 eq) dropwise at 60°C, tire resulting mixture was heated to 60°C for 1 hour. Hie mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL, 2x). The combined organic phase were washed with brine (10 mL*3), dried with anhydrous NazSCh, filtered and concentrated. The residue was purified by column chromatography (SiC , petroleum ether : ethyl acetate = 10: 1 to 3: 1, TLC) to give 30c. MS mass calculated for [M+l]+ (CnHnBrCTNii) required m/z 378.0, LCMS found m/z 378.2; ¾ NMR (400 MHz, CD3OD) d 7.34 (s, 3H) 7.21 (s, 1H) 6 28 (s, 1H) 3.01 (dt, J = 13.54, 6.74 Hz,
1H) 2.89 (dt, J = 13.72, 6.89 Hz, i l l ) 2.27 (s, 6H) 1.27 - 1.30 (m, 6H).
[0389] 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (30d). A solution of 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyiidazin-3-yl)acetonitrile (30c) ( 1 g, 2.78 mmol) in AcOH (30 mL), H2O (10 mL) and HC1 (40 mL) was heated to 120°C for 48 hours. LCMS showed the starting material was consumed and desired MS was detected. The mixture was adjusted to pH~7 with 3M NaQH at 15°C, tire solid was filtered and dried to give 30d, The product was used directly for the next step without further purification. MS mass calculated for [M+l]+ (CieHigBrNiO) required m/z 335.1, LCMS found m/z 335.2; Ή NMR (400 MHz, DMSO) 5 12.56 (s, 1H) 7.24 (s, 2H) 7.11 (s, 1H) 3.90 (s, 2H) 2.97 (quin, I = 6.82 Hz, 1H) 2.21 (s, 6H) 1.3 1 (d, J = 6.85 Hz, 6H).
[0390] 6-(4~((diphenylmethylene)amino)-2,6-dimethySbenzyS)-4-isopropylpyridazm- 3(2H)-one (30e), To a solution of 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyridazin- 3(2H)-one (30d) (100 mg, 298.30 umol) and benzophenone imine (54.06 mg, 298.30 umol,
50.06 uL) in dioxane (5 mL) was added t-BuONa (43.00 mg, 447.44 umol), Fd.TdbaL (27.32 mg, 29.83 umol) and Xantphos (17.26 mg, 29 83 umol). The mixture was degassed and purged with 2 for 3 times and stirred at 80°C for 16 hours. Hie mixture was partitioned between DCM (20 mL) and sat. aq. NH4CI solution (10 mL) and extracted with DCM a second time. The combined organic layers was washed with brine (10 mL*3), dried with anhydrous NarSCfi, filtered and concentrated in vacuum to give 30e. MS mass calculated for [M+l ]+ (C29H29N3O) required m/z 436.2, LCMS found m/z 436.4. The residue was used directly for the next step without further purification. [0391] 6-{4~am!5io-2,6-dimethy!benz S)-4-isopropylpyridazm-3{2H)-one (30f). A solution of 6-(4-((diphenylmethylene)amino)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (30e) (100 mg, 229.59 umol) in HCl/EtOAc (5 mL) was stirred at 15°C for 16 hr. LCMS showed desired MS was detected. The mixture was diluted with water 5 mL and added saturated aqueous ofNaHCCh to modified pH = 9~10. The suspension was extracted with EtOAc (15 mL*3), the combined organic layers were dried over anhydrous NaiSO-i, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCfe, petroleum ether : ethyl acetate) to give 30f, MS mass calculated for | \1 · i | (C16H21N3O) required m/z 272.2, LCMS found m/z 272 3; 'H NMR (400 MHz, CD3OD) d 6.89 (s, 1H) 6 48 (s, 21 1) 3 89 (s, 21 1 ) 3.04 (dt, J = 13.69, 6.72 Hz, 1 1 1 ) 2.18 (s, 51 ! ) 1.15 (d, J = 6.97 Hz, 61 1). [Q392] N-(4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenyl)- 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 30). To a mixture of 6-(4- amino-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (30f) ( 10 mg, 36.85 umol) in THF (1 mL) w¾s added TEA (14.92 mg, 147.41 umol, 20.52 uL) and 5-oxo-4H-l,2,4-oxadiazole-3- carbonyl chloride (4e) (10.95 mg, 73 70 umol) at 15°C. The mixture was stirred at 15°C for 0 5 hours. The mixture was concentrated in vacuum to give a residue. The residue was purified by Prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.225%FA)-ACN] ; B%: 30%-50%,12min) to give Example 30. MS mass calculated for
[M+lf (C19H21N5O4) required m/z 384 2, LCMS found m/z 384 2; 1 1 NMR (400 MHz,
CD3OD) d 7.41 (s, 2H) 7.02 (s, 1H) 4.86 (s, 19H) 4.02 (s, 2H) 3.07 (dt, J = 13.72, 6.77 Hz, 1H) 2.30 (s, 6H) 1.15 (d, J = 6.85 Hz, 6H).
Example 31: N-(4-((5-(bicyclo[l.l.l]pentan-l-yl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-3,5- dichlorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
Figure imgf000134_0001
Exa ple 31
[Q393] 4-(bicyclo[l.l.l]pentan-l-yl)-3,6-dichloropyridazine (31a). To a mixture of 3,6- dichloropyridazine (170 mg, 1.14 mmol) and bicyclo[ l . l. l ]pentane-l -carboxylic acid (134.35 mg, 1.20 mmol) in H2O (5 mL) was added AgN03 ( 193.84 mg, 1.14 mmol) and ammonium persulphate (286.44 mg, 1.26 mmol) and H2SO4 (335.75 mg, 3.42 mmol, 182.48 uL in H2O (2.5 mL) in one portion at 60°C under N2. The mixture was stirred at 70°C for 20 minutes. After cooling the mixture was extracted with ethyl acetate (5 mL*2), the organic phases were washed with NaHCCb (2 mL), brine (5 mL), then dried over NarSCL, filtered and concentrated. The residue was purified by column chromatography (S1O2, petroleum ether : ethyl acetate= 5: 1) to give 31a. Ή NMR (400 MHz, (1) 4)1)) d 7.62 (s, 1H), 2.66 (s, 1 1 1 ). 2.34 (s, 61 1).
[Q394] 4-((5-(bicydo[l.l.l]pentan-l-yl)-6-chloropyridazio-3-yI)oxy)-3,5-dichloroaniSine (31b). 4-(bicyclo[l . l . l]pentan-l-yl)-3,6-dichloropyridazine (31a) (150 mg, 697 42 umol) and 4- amino-2,6-dichlorophenol (124.15 mg, 697.42 umo) in DMSO (9 mL) was added K2CO3 (385.55 mg, 2.79 mmol) and Cui (79.69 mg, 418.45 umol) in one portion at 25°C under N2. The mixture was stirred at 90°C for 16 hours. The residue was partitioned between ethyl acetate (20 mL) and H2O (5 mL*2). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous NazSOy filtered and concentrated in vacuum. The solid was purified by prep- TLC (petroleum ether : ethyl acetate^ 3: 1) to give 31b. MS mass calculated for [MtT]+ (C15H12CI3N3O) required m/z 356.0, LCMS found m/'z 355.9.
[0395] N-(4-((5-(bicyclo[l.l.l]pentan-l-yl)-6-chloropyridazin-3-yI)oxy)-3,5- dichlorophenyl-)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (31c). To a mixture of 4-((5-(bicyclo[l . l . l]pentan-l-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (31b) (30 mg, 84.12 umol) in DCM (5 mL) was added TEA (25.54 mg, 252.36 nmol, 35.13 uL) and 5-oxo-4,5- dihydro-1, 2, 4-oxadiazole-3 -carbonyl chloride (4e) (18.74 mg, 126.18 umol) in one portion at 0°C under N2, and the reaction was stirred at 0°C for 30 minutes. The residue was diluted with water (5 mL) and extracted with DCM (10 mL, 2x). The combined organic layers were washed with brine (5 mL*3), dried with anhydrous NazSOy fdtered and concentrated in vacuum. The solid was purified by prep-TLC (petroleum ether : ethyl acetate = 1 : 1) to give 31c.
[0396] N-(4-((5-(bicyclo[l.l.l]pentan-l-yl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-3,5- dichlorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 31 ). To a mixture of N-(4-((5-(bicyclo[ 1.1.1 lpentan-1 -yl)-6-chloropyridazin-3-yl)oxy)-3,5- diehlorophenyl-)~5-oxo-4,5-dihydro~l ,2,4-oxadiazole~3-carboxamide (31c) (18 mg, 38.41 umol) in AcOH (3 ml.) was added NaOAc (15.75 mg, 192.03 umol) in one portion. Then the mixture was stirred at 120°C under N2 for 16 hours. Tlie mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna 08 100* 30mm*5um; mobile phase:
[water (0.225% FA)-ACN]; B%: 45%-75%,l0 min) to give Example 31. MS mass calculated for [M+lf (C18H13CI2N5O5) required m/z 450 0, LCMS found m/z 450.0; !H NMR (400 MHz, CD3OD) d 7.91 (s, 2H), 7.19 (s, 1H), 2.60 (s, 1H), 2.25 (s, 6H).
Example 32: N-(3,5-dichloro-4-((5-(l -hydroxypropyI)-6-oxo-l,6-dihydropyridazin-3- y!)oxy)phenyl)-5-oxo-4,5-dihydro-l, 2,· 4-oxadiazole- 3-carboxamide
Figure imgf000136_0001
[0397] l-(3,6-dichloropyridazin-4~yS)propan-l-o! (32a). To a solution of 3,6-dichloro- l,2,4,5-tetrazine (1 g, 6.62 mmol) in Tol. (10 mL) was added pent- l-yn-3-ol (1.11 g, 13.25 mmol, 1.14 mL) at 20°C. The mixture was stirred at 11 Q°C for 16 hours under sealed tube. LCMS showed desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether : ethyl acetate =
1 : 1) to give 32a. MS mass calculated for [M+l]+ (C7H8CI2N2O) required m/z 207.1, LCMS found m/z 207 0: H NMR (400 MHz, CDCb) d 7.79 (s, 1H) 4.94 (dt, I = 7.73, 3.77 Hz, 1H) 2.72 (d, I = 4.03 Hz, i l l ) 1.94 (dqd, J = 14.52, 7.39, 7.39, 7.39, 3.55 Hz, 11 1) 1.60 - 1.72 (m, 11 1) 1.06 (t, J = 7.34 Hz, 3H).
[0398] 3,6-dichloro-4-(l-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine (32b). To a solution of l-(3,6-dichloropyridazin-4~yl)propan-i~o] (32a) (140 mg, 676.14 umol) and DHP (284.37 mg, 3.38 mmol, 309.10 uL) in DCM (5 mL) was added TsOH (5.82 mg, 33.81 umol). The mixture was stirred at 20°C for 1 hour. LCMS showed desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. Tire residue was purified by prep- TLC (Si02, petroleum ether /ethyl acetate:=2: 1, TLC) to give 32b. MS mass calculated for i \! i j - (C12H16CI2N2O2) required m/z 291.2, LCMS found m/z 291.1; !H NMR (400 MHz, CDCb) d 7.71 (s, 1H) 7.56 (s, 1H) 4.95 - 5 00 (m, 1H) 4 78 (dd, J = 7.06, 3 97 Hz, 1H) 4.69 (dd, I = 5.40, 2.09 Hz, !H) 4.40 (t, J = 3.42 Hz, 1H) 3 85 - 4.03 (m, 2H) 3.54 - 3.55 (m, 1H) 3.45 - 3.62 (m, 21 i) 3.33 - 3.41 (m, i l l ) 2.04 - 2.10 (m, I I I ) 1.47 - 1.94 (m, 241 1) 1.05 (t, J = 7.39 Hz, 3H) 0.95 (t, J = 7.39 Hz, 3H).
[0399] 3,5-dichloro~4-((6-chSoro-5-(l~((tetrahydro~2H-pyran-2-yl)oxy)propyS)pyridazm- 3-yl)oxy)aniSine (32c). To a solution of 3,6-dichloro-4-(l-((tetrahydro-2H-pyran-2- yl)oxy)propyl)pyridazine (32b) ( 130 mg, 446.47 umol) and 4-amino-2,6-dichlorophenol (79.48 mg, 446 47 umol) in DMSO (5 mL) was added K2CO3 (246.83 mg, 1.79 mmol) and Cut (51.02 mg, 267 88 umol) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 16 hours under N2 atmosphere. LCMS showed desired MS. The mixture was diluted in EtOAc (5 mL) and filtrated, and tire filtration was partitioned between Ethyl acetate (5 mL) and H2O 3 ml,. The organic phase was separated, and the aqueous phase was extracted with EtOAc (5 mL). The combined organic phase was washed with brine ( 10 mL*2), dried with anhydrous NazSO y filtered and concentrated in vacuum. Hie residue was purified by Prep-TLC (petroleum ether : ethyl acetate =2: 1) to give 32c. MS mass calculated for [M+ l]
(C18H20CI3N3Q3) required m/z 432 7, LCMS found m/z 432.1;1H NMR (400 MHz, CDCb) d 7.48 (s, H ! ) 7.29 (s, 1 1 1 ) 6.68 (s, 21 1) 4.97 (dd, J = 7.46, 3.79 Hz, 1 1 1 ) 4.76 - 4.83 (m, i l l ) 4.46 (t, J = 3.30 Hz, 1H) 3.93 - 4.02 (m, i l l) 3.80 (far s, 21 1 ) 3.54 - 3.62 (m, 1H) 3.33 - 3.41 (m, 1H) 1.85 - 1.99 (m, 31 1) 1.66 - 1.83 (m, 4H) 1.06 (t, J = 7.34 Hz, 2H) 0.96 (t, J = 7.34 Hz, 21 1).
[Q400] N-(3,5-dich!oro-4-((6~chiorQ-5-(l~((tetrahydro~2H-pyran-2- yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3- carboxamide (32d). To a solution of 3,5-dichloro-4-((6-chloro-5-(l-((tetrahydro-2H-pyran-2- yl)oxy)propy3)pyridazin-3-y!)oxy)aniline (32c) (110 mg, 254.20 umol) in DCM (5 mL) was added TEA (77.17 mg, 762.60 umol, 106.15 uL) and 5 -oxo~4H~l , 2,· 4-oxadiazole-3 -carbonyl chloride (56.63 mg, 381.30 umol). The mixture was stirred at 20°C for 0.5 hours. LCMS showed desired MS The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether : ethyl acetate = 1: 1) to give 32d. MS mass calculated for [M+l]+ (C21H20CI3N5O6) required m/z 544.8, LCMS found m/z 544.6; !H NMR (400 MHz, CD3OD) d 7.97 (s, 2H) 7.64 (s, 1H) 4.83 (dd, J = 8.05, 3.20 Hz, 11 1) 3.92 (s, 1H) 1.87 - 1.97 (m, 21 1) 1 59 - 1.69 (m, 1H) 1.06 (t, .1 = 7.28 Hz, 3H). [0401] l-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-l,2,4-oxadiazole-3- carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (32e). To a solution of N -(3 ,5 -dichloro-4-((6-chloro-5 -( 1 -((tetrahydro-2H-pyran-2-yl)oxy)propyl) pyridazin-3 - yl)oxy)phenyl)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carboxamide (32d) (130 mg, 238 63 nmol, 1 eq) in HOAc (5 mL) was added NaOAc (97.88 mg, 1 19 mmol). The mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH to give 32e. MS mass calculated for | M · ! | (CisHisCkNsQ?) required m/z 484.2, LCMS found m/z 484.1. The crude product was used into the next step without further purification.
[0402] N-(3,5-dichloro-4-((5-(l-hydroxypropyl)-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l, 2, 4-oxadiazoIe- 3-carboxamide (Example 32). To a solution of l-(6-(2, 6-dichloro-4-(5-oxo-4, 5-dihydro- 1 ,2,4-oxadiazole-3-carboxamido) phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (32e) (1 15 rng, 237.48 umol) in MeOH (3 mL) and 1 ! O (0.5 mL) was added LiOH.HzO (1 M, 474.97 uL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water 5 mL. The suspension was extracted with EtOAc (30 mL*3), the combined organic layers were dried over anhydrous NaiSOy filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 30%-60%, 10min) to give Example 32. MS mass calculated for [M+l]+ (CieHiiCbNsOe) required m/z 442.2, LCMS found /z 442.0;‘H NMR (400 MHz, CDiOD) 5 7.92 (s, 2H) 7.47 (s, 1H) 4 85 (s, 29H) 4.74 (br d, I = 4 77 Hz, 1 1 1} 1.88 - 2.02 (m, 1H) 1.51 - 1.64 (m, !H) 1.02 (t, I = 7 40 Hz, 3H).
Example 32 PI and P2: N-(3,5-dichloro-4-((5-(l-hydroxypropyl)-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-cartaoxamide
Figure imgf000139_0001
[0403] N-(3,5-dichloro-4-((6-chloro-5-(l-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5- oxo~4,S~dihydro-l,2,4-oxadiazo!e-3~carboxamide (32f). A solution ofN-(3,5~dichloro~4~((6- chloro-5-(l-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5- dihydro-l,2,4-oxadiazole-3-carboxamide (32d) (160 mg, 293.70 umol) in TFA (1 niL) and DCM (3 mL) was stirred at 20°C for 2 hours Tire reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column:
Phenomenex Luna C18 100*30mm* 5um; mobile phase: [water (0.2%FA)-ACN]; B%: 35%- 65%, l0min) to give 32f. MS mass calculated for [M+l]+ (CieHuCbNsOs) required m/z 460.0, LCMS found m/z 460 1.
[0404] SFC separation, N-(3,5-dichloro-4-((6-chloro-5-(l-hydroxypropyl)pyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (32f) (95 mg, 206.23 umol) was separated by SFC (column: DAICEL CHDRALCEL OJ (250mm*30mm,10um); mobile phase: [0.1%NH3*H2O MeOH]; B%: 30%-30%,5min) to give 32f-Pl and 32f-P2.
[0405] (R)-N-(3,5-dichloro-4-((5-(l-hydroxypropyl)-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 32-PI). A solution of (R)~N-(3,5~dichloro~4-((6-ch]oro-5-(l-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5- oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (32f-Pl ) (10.00 mg, 21 71 umol) in HOAc (2 mL) and H2O (0.1 mL) was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 200*40mm* !Oum; mobile phase: [water (0.225%FA)-ACN]; B%: 20%-50%, l2min) to give Example 32-PI . MS mass calculated for [M+l]+
(C16H1.3CI2N5O6) required m/z 442.0, LCMS found m/z 442.0; 1 1 NMR (400 MHz, CD3OD) d 7.92 (s, 2H) 7.47 (d, J = 0.98 Hz, 1H) 4.87 (s, 40H) 4.73 (br d, J = 4.03 Hz, 1H) 1.90 - 1.98 (m, 1H) 1.58 (dt, J = 14.15, 7.29 Hz, 1 1 !) 1.02 (t, I = 7.40 Hz, 3H).
[Q406] (S)-N-(3,5-dichloro-4-((5-(l -hydroxypropyl)-6-oxo-l,6-dihydropyridazin-3- yI)oxy)pheny!)-5-oxo-4,5-dihydro-l, 2, 4-oxadiazo!e- 3-carboxamide (Example 32-P2). A solution of (S)-N-(3,5-dichloro-4-((6-chloro-5-(l-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5- oxo-4, 5-dihydro-1 , 2, 4-oxadiazole-3-carboxamide (32f-P2) (10 00 mg, 21 .71 umol) in HOAc (2 mL) and H2O (0.1 mL) was stirred at 120°C for 16hr. Tlie reaction mixture was concentrated under reduced pressure to give a residue. Hie residue was purified by Prep-HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.2%FA)-ACN]; B%: 20%- 50%,10min to give Example 32-P2. MS mass calculated for [M+l] + (CieHiiChNsOe) required m/z 442.0, LCMS found m/z 442.0; Ή NMR (400 MHz, CD3OD) d 7.91 (s, 2H) 7.47 (d, J = 1.10 Hz, 1H) 4.87 (s, 19H) 4.73 (dd, J = 7.09, 3.06 Hz, 1H) 1.95 (ddd, J = 13.91, 7.43, 3.48 Hz, 1H) 1 .52 - 1.63 (in, 1H) 1.02 (t, J = 7.34 Hz, 3H).
Example 33: N-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-l,6-dihydropyridazin-3- y!)oxy)phenyl)-5-oxo-4,5-dihydro-l , 2,· 4-oxadiazole- 3-carboxamide
Figure imgf000141_0001
[0407] 2-(3,0-dkMoropyridazm-4~y!)propan-2~oS (33a), To a solution of 3,6-dich loro- 1, 2,4, 5-tetrazine (500 mg, 3.31 mmol) in Tol. (5 rriL) was added 2-methylbut-3-yn-2-ol at 20°C.
The mixture was stirred at 115°C for 16 hours under sealed tube. LCMS showed desired MS.
The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether : ethyl acetate:= 10: 1 to 4: 1 ,TLC) to give 33a. MS mass calculated for [M+l]+ (CTHKCIINIO) required m/z 207.0, LCMS found m/z 207.0; H NMR (400 MHz, CDCb) d 7.98 (s, 1H) 2.17 (s, 1H) 1.77 (s, 6H).
[0408] 3,6-dichloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazine (33b). To a solution of 2-(3,6-dichloropyridazin-4-yl)propan-2-oi (33a) (70 mg, 338.07 umol) in DCM (5 niL) was added DHP ( 142.19 mg, 1.69 mmol, 154.56 uL) and PPTS (16.99 mg, 67.61 umol). The mixture was stirred at 20°C for 16 hours. Hie mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL, 2x). The combined organic layers were washed with brine (10 mL*3), dried with anhydrous NaiSOi, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (Si02, petroleum ether : ethyl acetate= 5: I .Tl .(') to give 33b, MS mass calculated for [M+l]+ (C12H16CI2N2O2) required m/z 291.1, LCMS found m/z 291.1; T-Ϊ NMR (400 MHz, CDCb) d 7.85 (s, 1H) 4.84 (dd, I = 5.62, 2.81 Hz, 1H) 4.01 - 4.08 (m, I I I) 3.88 - 3.95 (m, 1H) 3.57 (dt, J = 11.13, 5.44 Hz, 1H) 3.47 (dt, J = 11.37, 5.69 Hz, 1H) 1.83 - 1.96 (m, 2H) 1.78 (s, 3H) 1.75 (s, 31 1) 1.56 - 1 .73 (m, 6H). [0409] 3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2- yl)pyridazin-3-yl)oxy)aniline (33c). To a solution of 3,6-dichloro-4-(2-((tetrahydro-2H-pyran-
2-yl)oxy)propan-2-yi)pyndazine (33b) (40 mg, 137.38 umol) and 4-ammo-2,6-dichlorophenol (24.45 mg, 137.38 umol) in DMSO (4 mL) was added K2CO3 (75.94 mg, 549.50 umol) and Cul (15 70 mg, 82.43 umol) was degassed and purged with N2 for 3 times, and then the mixture was stiixed at 90°C for 16 hours under N2 atmosphere LCMS showed desired MS. The mixture was diluted in EtOAc (5 mL) and filtered. The filtrate was partitioned between ethyl acetate (5 mL) and H2O (3 mL) The organic phase was separated, and the aqueous phase was extracted with EtOAc (5 mL). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The mixture vras purified by Prep- TLC (petroleum ether : ethyl acetate= 3: 1) to give 33c. MS mass calculated for [M+l] + (C18H20Q3N3O3) required m/z 432 1, LCMS found m/z 432.1.
[0410] N-(3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2- yl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (33d). To a solution of 3 ,5 -dichloro-4-((6-chloro-5 -(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2- yl)pyridazin-3-yl)oxy)aniiine (33c) (25 mg, 57.77 umol) hr DCM (1 .5 mL) was added TEA (17.54 mg, 173.32 umol, 24.12 uL and 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carbonyl chloride (4e) (12.87 mg, 86.66 umol). The mixture was stirred at 20°C for 0.5 hours. LCMS showed desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC , petroleum ether : ethyl acetate) to give 33d. MS mass calculated for [M+l]+ (C21H20CI3N5O6) required m/z 544.0, LCMS found m/z 544.1; *H NMR (400 MHz, CD3OD) d 7.98 (s, 21 !) 7.76 (s, 1H) 4.36 - 4.41 Cm. 6H) 3.93 (s, 3H) 3.83 - 3.89 (m, 1H) 3.62 - 3.65 (m, 2H) 3.59 (t, I = 6.60 Hz, 5H) 3.48 (dt, J = 7.73, 6.22 Hz, 9H) 1.92 (dt, I = 6.14, 3.10 Hz, 4H) 1.78 - 1.88 (rn, 16H) 1.66 - 1.75 (m, 9H).
[0411] N-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l, 2,· 4-oxadiazole- 3-carboxamide (Example 33). A solution ofN-(3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)pyridazin-3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (33d) (25 mg, 45.89 umol) in HOAc (2 mL) and H2O (0.1 mL) was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 200*40mm* lOum; mobile phase: [water (0.225%FA)-ACN [; B%: 20%-55%, 12mm) to give Example 33. MS mass calculated for [M+l]+ (CieHisChNsOe) required m/z 442.0, LCMS found m/z 441.9; 1H NMR (400 MHz, CD3OD) d 7.91 (s, 2H) 7.58 (s, 1H) 4.85 (hr s, 126H) 1 62 (s, 6H). Example 34: N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyI)-5-oxo-4, 5-dihydro- 1 , 2,· 4-oxadiazole- 3-carboxamide
Figure imgf000143_0001
[0412] 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropylpyridazin-3(2H)-one (34a). To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (8b) (300 mg, 954.9! umol) in CLLCN (10 mL) and THF (10 mL) was added NaHCO (240.66 mg, 2.86 mmol, 111.41 uL). Then Select F (372.11 mg, 1.05 mmol) was added to the mixture in portions at 20°C. Then the mixture was stirred at 20°C for 2 hours. The mixture was diluted with EtOAc (30 mL) and HiO (30 mL). The organic layer was washed with brine (10 mL), dried in vacuum. The residue was purified by Prep-TLC (petroleum ether : ethyl acetate=l : 1) to give 34a. ’Ή NMR (400 MHz, CDiOD) 5 7.29 (d, J = 0.86 Hz, 1H) 6.89 (d, J = 8.44 Hz, 1H) 3.10 - 3.23 (m, 1H) 1 2.5 - 1.33 (m, 6H).
[0413] N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3- yI)oxy)pheny!)-5-oxo-4,5-dihydro-l, 2,· 4-oxadiazole- 3-carboxamide (Example 34). To a solution of 6-(4-amino-2,6-dichloro-3 -fluorophenoxy)-4-isopropy lpyridazin-3 (2H)-one (34a) (100 mg, 301 06 umol) in DCM (4 mL) was added TEA (91.39 mg, 903.19 umol, 125 71 uL) and 5~oxo-4H-l,2,4-oxadiazole-3~carbony! chloride (4e) (67.06 mg, 451 59 umol). The mixture was stirred at 20°C for 0.5 hours. LCMS showed desired MS. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC , petroleum ether : ethyl acetate) to give the desired material. Tire desired compound was re-purified by Prep-HPLC (column: Phenomenex Luna C18 200*40mm* lOum; mobile phase: [water (0.225%FA)-ACN];B%: 20%-60%,12mm) to give Example 34. MS mass calculated for i M · i | (C 16H12C12FN505) required rn/z 444.0, LCMS found m/z 443.9; ¾ NMR (400 MHz, CDsOD) d 7.97 (br d, J = 6.72 Hz, 1H) 7.37 (s, 1H) 4.87 (br s, 13H) 3.12 - 3.22 (m, ITT) 1.28 (br d, J = 6.60 Hz, 6H). Scheme F : 4-((5-( l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyridazin-3-yl)oxy)-
3,5~dich!oroandine (Compound 35c)
Figure imgf000144_0001
[0414] 2-(3,6-dich!oropyridazin-4-y!)propan-l-oS (35a), To H2O (25 niL) was added TFA (4.97 g, 43.63 mmol, 3.23 mL) at 50°C, then 2-methyipropane-l,3~diol (6.65 g, 73.8 mmol, 6.59 mL) was added in the mixture, followed by addition of 3,6-dichloropyridazine (5 g, 33.6 mmol) and AgNCb (7.70 g, 45 3 mmol). Then a solution of ammonia hydrogen thiosulfate (15.3 g, 67.1 mmol, 14.6 mL) in H2O (15 mL) was added in the mixture in portions at 50 °C, and the resulting mixture was stirred at 50 °C for 0.5 hours. The reaction mixture was partitioned between H2O (45 mL) and EtOAc (50 mL). The organic phase was separated, washed with H2O (50 mL* 3), dried oxer NaiSOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate) to give 35a. MS mass calculated for [M+l]+ (C7H8CI2N2O) requires m/z 207.0, LCMS found m/z 207.0; Tl NMR (400 MHz, CDCb) d 7.52 (s, 1H), 3 93 - 3.84 (m, 2H), 3 45 - 3.30 (m, 1H), 1.35 (d , ./
= 7.2 Hz, 31 1).
[0415] 4-(l-((tert-butyldimethylsilyl)oxy)propan-2-yI)-3,6-dichIoropyridazine (35b). To a solution of 2-(3,6~dichloropyridazin~4-yl)propan-l-oi (35a) (3.4 g, 16.4 mmol) and tert-butyl- chloro-dimethy] -silane (2.47 g, 16.4 mmol, 2.01 mL) in DMF (25 mL) was added imidazole (1.34 g, 19.7 mmol). The mixture was stirred at 25°C for 1 hr under N2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL* 3). The combined organic phase was washed with brine (50 mL* 2), dried with anhydrous NaeSCb, filtered and concentrated in vacuum to give 35b. The product was used directly in the next step without further purification. MS mass calculated for [M+l]+ (C13H22CI2N2OS1) requires m/z 321.1, LCMS found m/z 321.0; 1 1 N M R (400 MHz, CDCb) d 7.48 (s, 1H), 3.77 (d, ./= 4.4 Hz, 2H), 3.38 - 3.29 (m, 1H), 1 .32 (d, J= 6.8 Hz, 3H), 0 88 - 0.79 (m, 9H), 0.04 - 0 02 (m, 3H), 0.02 - 0.08 (m, 3H).
[0416] 4-((5-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropyridazin-3-yl)oxy)- 3,5-dichloroaniline (35c), To a solution of 4-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3,6- dichloropyridazine (35b) (1 g, 3.11 mmol) in DMSO (15 mL) was added 4-ammo-2,6~ dichlorophenol (752.84 mg, 3.11 mmol), K2CO3 (1.29 g, 9.34 mmol) and Cul (355.63 mg, 1.87 mmol). The mixture was stirred at 90 °C under N2 atmosphere for 5 hours. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOAc (50 mL). The reaction mixture was quenched by addition H2O (30 mL), and then extracted with ethyl acetate (50 ml.) and extracted with EtOAc (50 mL * 5). The combined organic layers were washed with brine (50 mL * 2), dried over NarSOr, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, petroleum ether: ethyl acetate) to give 35c. MS mass calculated for [MHH j^CiHfceCblSbOiSi) requires m/z 462.1, LCMS found m/z 462.1.
Example 35: N-(3,5-dichloro-4-((5-(l-hydroxypropan-2-yl)-l-methyl-6-oxo-1 ,6- dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4, 5- dihydro-1, 2, 4-oxadiazole-3-carboxamide
Figure imgf000145_0001
[0417] 2-(6-(2,6-dichloro-4-(l,3-dioxoisoindolin-2-yl)phenoxy)-3-oxo-2,3- dihydropyridazin-4-yl)propyl acetate (35d). To a solution of 4-((5-(l~((tert- butyldimethylsilyl)oxy)propan-2-yl)-6-ch]oropyridazin-3-yl)oxy)-3,5-dichloroaniline (35c) (510 mg, 1.10 mmol) in HOAc (8 mL) was added isobenzofuran-1, 3-dione (244.8 mg, 1.65 mmol) and NaOAc (271.2 mg, 3.31 mmol). The mixture w'as stirred at 120°C for 16 hours. Hie reaction mixture was concentrated under reduced pressure to remove HOAc. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL * 3). Hie combined organic layers were washed with brine (30 mL), dried over NaiSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate) to give 35d MS mass calculated for [M+l j^CiiHriCliALOe) requires m/z 502.0, LCMS found m/z 502.1.
[0418] 2-(6-(2,6-dichIoro-4-(l,3-dioxoisoindolin-2-yl)phenoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)propyl acetate (35e). To a solution of 2-(6-(2,6-dichloro-4-(l ,3- dioxoisoindolin-2-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35d) (230 mg, 457.9 umol) in DMF (3 mL) was added K2CO3 ( 107.6 mg, 778.4 umol) and Mel (130.0 mg,
915.8 umol, 57.0 uL). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched by addition H2O (15 mL) at 25 °C, and then extracted with EtOAc (15 mL* 3). The combined organic layers were washed with brine (30 mL), dried over NazSOr, filtered and concentrated under reduced pressure to give 35e. The mixture was used into the next step without further purification. MS mass calculated for [M+l]+ (C24H19CI2N3O6) requires m/z 516.1, LCMS found m/z 516.1
[0419] 6-(4-amino-2,6-dichlorophenoxy)-4-(l-hydroxypropan-2-yl)-2-methylpyridazin- 3(2H)-one (35f). To a solution of 2-(6-(2,6-dichloro-4-(l,3-dioxoisoindolin-2-yl)phenoxy)-2- methyl-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35e) (223 mg, 431.89 umol) in MeOH (5 mL) was added butan-l-amine (1.1 1 g, 15.2 mmol, 1.5 ml,). The mixture was stirred at 70 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove MeOH. Hie residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate) to give 35f. MS mass calculated for [M+l]+ (C14H15CI2N3O3) requires m/z 344.0, LCMS found m/z 344 0.
[042Q] N-(3,5-dichloro-4-((5-(l-hydroxypropan-2-yl)-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 35). To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-(l-hydroxypropan-2-yl)-2- methylpyridazin-3(2H)-one (35f) (50 mg, 145.3 umol) in THE (3 mL) w¾s added TEA (44.1 mg,
435.8 umol, 60.7 uL) and 5-oxo-4H-l,2,4-oxadiazole-3-carbonyl chloride (32.4 mg, 217.9 umol). The mixture was stirred at 25 °C for 5 minutes. TLC and LCMS showed 35f was consumed completely and desired mass + Ac was detected. The reaction mixture was quenched by addition of MeOH (5 mL) at 25°C. Then the pH w¾s adjusted to 10-12 with LiOHLEO, and tire resulting mixture was stirred at 25 °C for 1 hour. LCMS showed the desired MS was found in the major peak. Then the mixture was concentrated in vacuum, and the residue was purified by prep-HPLC (column : Waters Xbridge Prep OBD C18 150*40mm* l0um; mobile phase: [water (lOmM NH4HC03)-MeCN]) to give Example 35. MS mass calculated for [M+l]+ (CnHisC NsOe) requires m/z 456.0, LCMS found m/z 456.1; ¾ NMR (400 MHz, CD3OD) d 7.93 (s, 2H), 7.34 (s, 1H), 3.80 (dd, J= 6 0, 10.6 Hz, 1 1 1).. 3.73 - 3.66 (m, 1 1 1). 3.51 (s, 3H), 3 29 - 3.23 (m, 1H), 1.29 (d, J= 7.0 Hz, 3H). Example 36: N-(3,5-dichloro-4-((5-(l-hydroxypropan-2-yl)-6-oxo-l,6-dihydropyridazin-3- y!)oxy)phenyl)-5~oxo-4,5-dihydro-l , 2, 4-oxadiazole- 3-carboxamide
Figure imgf000147_0001
[0421] N-(3,5-dichloro-4-((6-chloro-5-(l-hydroxypropan-2-yl)pyridazin-3-yl)oxy)phenyl)- 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-cartaoxamide (36a). To a solution of 4-((5-(l-((tert- butyldimethylsilyl)oxy)propan-2-y])-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (35c) (50 mg, 108.0 umol) in THE (2 mL) was added TEA (32.8 mg, 324.0 umol, 45.1 uL) and 5-oxo-4H- l,2,4-oxadiazole-3-carbonyl chloride (24.1 mg, 162.0 umol). The mixture was stirred at 25 °C for 5 minutes. The reaction mixture was quenched by addition of MeOH (25 mL) at 25 °C, and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether: ethyl acetate) to give 36a. MS mass calculated for i M · 1 1 ( CieHnCbN Q ) requires rn/z 460.0, LCMS found m/z 460.0.
[Q422] 2-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-l,2,4-oxadiazole-3- carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl formate (36b). To a solution of N-(3,5-dichloro-4-((6-chloro-5-(l-hydroxypropan-2-yl)pyridazin-3-yl)oxy)phenyl)- 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (36a) (40 mg, 86.8 umol) in HCOOH (5 mL) was stirred at 100 °C for 16 hours Hie reaction mixture was concentrated under reduced pressure to remove HCOOH. The residue was purified by prep-TLC (SiOr, ethyl acetate:
petroleum ether) to give 36b. MS mass calculated for [M+l]+ (C17H13Q2N5Q7) requires m/z 470.0, LCMS found m/z 470.0.
[0423] N-(3,5-dich!oro-4-((5~(l-hydroxypropan-2-y!)~0-oxo-l,6~dihydropyridazin~3- yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 36). To a solution of 2-(6-(2, 6-dichloro-4-(5-oxo-4, 5-dihydro- 1,2, 4-oxadiazole-3-carboxamido)phenoxy)-
3-oxo-2,3-dihydropyridazin-4-y])propyl formate (36b) (35 mg, 74.4 umol) in MeOH (4 mL) was added L1OH.H2O (3 8 mg, 89.3 umol) in H2O (1 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue -was purified by prep-HPLC (column: Waters Abridge BEH C18 100*30mm* 10um: mobile phase: pater (l OmM NH4HC03)-MeCN]) to give Example 36. MS mass calculated for [M+1 ] (C16H13C12N506) requires m/z 442.0, LCMS found m/z 442.1 , TT NMR (400 MHz, CD3OD) 6 7.91 (s, 1H), 7.36 (s, i l l). 3.84 - 3.78 (m, 1H), 3.73 - 3.67 (m, 1H), 3.26 - 3.20 (m, 1H), 1.30 (d, J= 7.0 Hz, 3H).
Example 37: N-(3,5-dieh!oro~4-((5-(2~hydroxypropan~2-yI)~l-methyl-6-oxo-l,6- dihydropyridazio-3-yI)oxy}phenyl)-S-oxo-4,5-dihydro-l,2,4-oxadiazoSe-3-carboxamide
Figure imgf000148_0001
[0424] 2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoindoline-l,3-dione (37a). To a mixture of 3,5-dichloro-4-((6-chloro-5-(2- ((tetrahydro-2H-pyran-2~y3)oxy)propan-2-yi)pyridazin-3-yl)oxy)aniline (33c) (100 mg, 231.1 umol) and isohenzofuran~l,3~dione (37.7 mg, 254.2 umol) in HOAc (2 mL) was added NaOAc (94.8 mg, 1.16 mmol) under Ni. Hie mixture was stirred at 120 °C for 16 hours. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous NaiSCp filtered and concentrated in vacuum. The residue was purified by prep-TLC (Sith, petroleum ether/ethyl acetate) to give 37a. MS mass calculated for [M+ ip C21H15CI2N3O5) requires m/z 460.0, MS mass found m/z 460.0; !H NMR (400 MHz, CDCb) d 9 91 (br s, 2H), 8.11 - 7.93 (m, 2H), 7.92 - 7.74 (m, 3H), 7.61 (d, J= 1.6 Hz, 3H), 7 30 - 7.28 (m, 1H), 2.16 - 2 00 (m, 3H), 1 .90 - 1.84 (m, 2H), 1.68 (br d, J= 6.0 Hz, H i ). 1.67 - 1.65 (m, I I I). 1.67 - 1.65 (rn, 1H), 1.66 (s,
1H). [0425] 2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)isoindoline-l,3-dione (37b). To a mixture of 2-(3,5- dichloro-4-((5 -(2-hy droxypropan-2~yi)-6~oxo- 1 ,6-dihydropyridazin-3 - yl)oxy)phenyl)isoindoline-l,3-dione (37a) (50 mg, 108.6 umol) in DMF (3 mL) was added K2CO3 (30.0 mg, 217.3 umol) and Mel (30.8 mg, 217.3 umol, 13.53 uL) under N2. The mixture was stirred at 20 °C for 1 hour. The reaction was poured into water (5 mL). The aqueous phase was extracted with EtOAc (15 mL* 2). The combined organic phase was washed with brine (10 mL* 2), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate) to give 37b. MS mass calculated for [M+ir (C22Hi7Cl2N30s) requires m/z 474.1, MS mass found m/z 474.1.
[Q426] 6-(4-amino-2,6-dichlorophenoxy)-4-(2-hydroxypropan-2-yl)-2-methylpyridazin- 3(2H)-one (37c). To a mixture of 2-(3,5-dichloro-4~((5-(2-hydroxypropan~2-y!)~l-methyl-6- oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-l,3-dione (37b) (30 mg, 63.3 umol) in MeOH (1.5 mL) was added n-butylamine (11.6 mg, 158.1 umol, 15.63 uL) under N2. The mixture was stirred at 70 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Tire residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate) and the obtained crude product was re-purified by prep-HPLC (column: Waters Abridge BEH C18 100s 30mm * 10um: mobile phase: [water (lOmM NHiHCQiVMeCN ]) to give 37c. ¾ NMR (400 MHz, CDCb) d 7.20 - 7.08 (m, 1H), 6 75 - 6.62 (m, 2H), 5 68 - 5.51 (m, 1H), 3.85 - 3.71 (m, 2H), 3.63 - 3.50 (m, 3H), 1.62 (s, 6H).
[0427] N-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-l-methyI-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide (Example 37). To a mixture of 6-(4-amino-2,6-dichlorophenoxy)-4~(2-hydroxypropan-2-yl)-2- methylpyridazin-3(2H)-one (37c) ( 10 mg, 29.05 umol) in THF (2 mL) was added TEA (8.82 mg, 87.12umol, 12.1 uL) and 5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carbonyl chloride (12.9 mg, 87.2 umol) under N2. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue Hie residue was purified by prep-HPLC (column: Welch Ultimate AQ-C18 150* 30mm*5um; mobile phase: [water (0.1%TFA)-MeCN]) to give Example 37. MS mass calculated for [M+l]+ (C17H15CI2N5O6) requires m/z 456.0, MS mass found m/z 456.0; Ή NMR (400 MHz, CD3OD) d 7.96 - 7.88 (m, 2H), 7.60 - 7.52 (m, 1H), 4.46 - 4.37 (m, 1H), 3.68 - 3.59 (m, 1H), 3.53 - 3.47 (m, 1H), 3.50 - 3.47 (m, 1H), 3.49 (s, 1H), I .94 - 1.84 (m, 1H), 1.66 - 1.54 (m, 6H). Biological Example: Biological Screening
Example Bl: Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay for Thyroid Hormone Receptor Agonist Screening
[Q428] LanthaScreen™ TR-FRET Thyroid Receptor alpha Coactivator Assay kit
(TherrnoFisher) and LanthaScreen™ TR-FRET Thyroid Receptor beta Coactivator Assay kit (ThermoFisher) were used for agonist compound screening. Compounds in DMSQ were diluted using ECHO Liquid Handler (Labcyte Inc.) into 384 plates in 10-point 3-fold series in duplicate (5 micro M final top concentration). Buffer C (ThennoFisher) was added to each well before the 4x mixture of fluorescein-SCR2-2 coactivator (200nM final concentration), Terbium-labeled anti-GST antibody (2nM final concentration), and TR alpha-LBD (0.4nM final concentration) or TR beta-LBD (l.OnM final concentration) was added. After 2 hour incubation at room temperature in dark, the TR-FRET signal was measured on an EnVision plate reader
(PerkinElmer) with excitation at 340 nm and dual emission readout at 495 and 520 nm with the delay time of 100 micro second and the integration time of 200 micro second. The ratio of emission signal at 520 and at 495 was used to calculate ECso using GraphPad Prism (GraphPad Software). In every batch of compound screening, T3 (L-3, 3’,5-Triiodothyronine sodium salt, >95%) (Calbiochem) was used as reference compound. Hie ECso of T3 measured were within 3- fold of the reference value provided by the assay kit manufacturer (ThermoFisher Scientific).
The Z’ factors measured in every batch of screening using T3 as high percent effect (HPE) control and 0.5% DMSO as zero percent effect (ZPE) control were in the range of 0.5 to 0.8. Compounds’ THR-beta selectivity values are derived from T3 -selectivity normalized data. Data obtained using the TR-FRET assay for certain compounds disclosed herein are listed in Table 2.
Table 2.
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
n.a. denotes not applicable; a all compounds were ran in duplicate multiple times, anc the average data is reported
[0429] All publications, including patents, patent applications, and scientific articles, mentioned in this specification are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, including patent, patent application, or scientific article, were specifically and individually indicated to be incorporated by reference.
[0430] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled m the art that certain minor changes and modifications will be practiced in light of the above teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

Claims
Claim 1. A compound of formula (I):
Figure imgf000153_0001
or a pharmaceutically acceptable salt thereof, wherein; ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from tire group consisting of N, O, and S, wherein the heterocycle is optionally substituted with 1-2 C1-C3 alkyl or C3-C4 cycloalkyl groups, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
R’! is C1-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups, C3-C5 cycloalkyl,
Figure imgf000153_0002
R2 is H or C1-C3 alkyl;
L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(Ri l)CN, CHR11, or C(R] ])RU;
R3 and R4 are independently Cl, Br, methyl, or ethyl;
R5 is H, halo, Ci-Cr alkyl, or C3-C4 cycloalkyl; or R5 together with R4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
X is absent, O,
CR!2Ri2NR]
Figure imgf000153_0003
, each R10 is independently C1-C3 alkyl or H; each R11 is independently C1-C2 alkyl optionally substituted with 1-5 halo, or two R11 groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring; and each R1 2 is independently H or methyl.
Claim 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is of formula (IIA) or (IIB):
Figure imgf000154_0001
wherein R 1, R2, R3, R4, R5, X, and L are as defined in claim 1.
Claim 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is of formula (VD):
Figure imgf000154_0002
wherein R1, R2, R3, R4, and R5 are as defined in claim 1.
Claim 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein:
R! is Cl -C4 alkyl optionally substituted with 1-2 halo or hydroxyl groups, or C3-C5
cycloalkyl.
Claim 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein:
R: is isopropyl, t-butyl, HO-CH(CH3)
1 10-0 I2 1 UCi k)-. cyclopropyl, o
Figure imgf000155_0001
Claim 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherem:
R2 is H or -CH3.
Claim 7 The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein:
R3 is chloro or -CH3.
Claim 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein:
R4 is chloro or -CH3;
or R5 together with R4 and the intervening atoms form a 5-6 membered cycloalkyl.
Claim 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: R5 together with R4 and tire intervening atoms form cyclopentyl.
Claim 10. The compound of any one of claims 1 -8, or a pharmaceutically acceptable salt thereof, wherein:
R5 is H or fluoro.
Claim 11. The compound of any one of claims 1 , 2, and 4- 10, or a pharmaceutically acceptable salt thereof, wherein:
X is a bond. Claim 12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000156_0001
each R12 is independently H or methyl.
Claim 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein:
X is -OCHi-, -NHCH2-, -NHC(O)-, -MCI MCI !.·-. or -N(H)CH(CH3)-.
Claim 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein:
1. is O, (T 1 ·. SO2, CO, CHR ; ;. or C(Rn)Rn; and
each R11 is independently methyl or ethyl.
Claim 15 Tire compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:
L is O, CH2, SO2, or CO.
Claim 16. A compound of formula (I-a):
Figure imgf000156_0002
(I-a)
or a tautomer or an N -oxide thereof, or an isotopomer of each thereof, or a prodrag of each of the above, or a stereoisomer of tire aforesaid, or a pharmaceutically acceptable salt of each of the foregoing, or a solvate of each of the preceding, wherein: ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted with 1 -2 C1-C3 alkyl or C3-C4 cycioalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom attached to
R! is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1-5 halo; C3-C5 cycloalkyl,
CON(R!0)2, or NR10COR10, wherein each Ri0 is independently C1-C3 alkyl or H;
R2 is H or Ci-C3 alkyl;
L ss O, CH2, S, SO, SO2, CO, CHF, CF2, C( R )CN. CHR11, or C(R] ])RU, wherein each R1 1 is C1-C2 alkyl optionally substituted with 1-5 halo, or the 2 RI ! groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring; each of R3 and R4 is independently Cl, Br, methyl, or ethyl;
R3 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl, or R3 together with R4 and the intervening atoms form a 5-7 membered cycioalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
X is absent, or is O, NR12, C(0)NR12, NR12C(0), CR12R12, OCR12R12, CR12R120,
NR] 2CRt2R12, CRi2R]2NR!2 , SO2NR12, or NR]2SCh, wherein each R! 2 is independently H or methyl.
Claim 17. A compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
Claim 18. A pharmaceutical composition comprising the compound of any one of claims 1- 17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Claim 19. A method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting either an effective amount of the compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof or an effective amount of the pharmaceutical composition of claim 18, with the THR beta.
Claim 20. A method of treating a disorder which is mediated by TOR beta in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 18. Claim 21. The method of claim 20, wherein the disorder is non-alcoholic steatohepatitis (NASH).
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AU2019325656A1 (en) 2021-03-11
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